Novel substituted sulfoximine compounds as indoleamine 2,3-dioxygenase (ido) inhibitors

ABSTRACT

Compounds of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof: (I). Also disclosed herein are uses of the compounds disclosed herein in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising a compound disclosed herein. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.

BACKGROUND OF THE INVENTION

Tryptophan (Trp) is an essential amino acid required for thebiosynthesis of proteins, niacin and the neurotransmitter5-hydroxytryptamine (serotonin). The enzyme indoleamine 2,3-dioxygenase(IDO) catalyzes the first and rate limiting step in the degradation ofL-tryptophan to N-formyl-kynurenine. In human cells, a depletion of Trpresulting from IDO activity is a prominent gamma interferon(EFN-γ)-inducible antimicrobial effector mechanism. IFN-γ stimulationinduces activation of IDO, which leads to a depletion of Trp, therebyarresting the growth of Trp-dependent intracellular pathogens such asToxoplasma gondii and Chlamydia trachomatis. IDO activity also has anantiproliferative effect on many tumor cells, and IDO induction has beenobserved in vivo during rejection of allogeneic tumors, indicating apossible role for this enzyme in the tumor rejection process (Daubener,et al, 1999, Adv. Exp. Med. Biol, 467: 517-24; Taylor, et al, 1991,FASEB J., 5: 2516-22).

It has been observed that HeLa cells co-cultured with peripheral bloodlymphocytes (PBLs) acquire an immuno-inhibitory phenotype throughup-regulation of IDO activity. A reduction in PBL proliferation upontreatment with interleukin-2 (IL2) was believed to result from IDOreleased by the tumor cells in response to IFN-γ secretion by the PBLs.This effect was reversed by treatment with 1-methyl-tryptophan (IMT), aspecific IDO inhibitor. It was proposed that IDO activity in tumor cellsmay serve to impair antitumor responses (Logan, et al, 2002, Immunology,105: 478-87).

Several lines of evidence suggest that IDO is involved in induction ofimmune tolerance. Studies of mammalian pregnancy, tumor resistance,chronic infections and autoimmune diseases have shown that cellsexpressing IDO can suppress T-cell responses and promote tolerance.Accelerated Trp catabolism has been observed in diseases and disordersassociated with cellular immune activation, such as infection,malignancy, autoimmune diseases and AIDS, as well as during pregnancy.For example, increased levels of IFNs and elevated levels of urinary Trpmetabolites have been observed in autoimmune diseases; it has beenpostulated that systemic or local depletion of Trp occurring inautoimmune diseases may relate to the degeneration and wasting symptomsof these diseases. In support of this hypothesis, high levels of IDOwere observed in cells isolated from the synovia of arthritic joints.IFNs are also elevated in human immunodeficiency virus (HIV) patientsand increasing IFN levels are associated with a worsening prognosis.Thus, it was proposed that IDO is induced chronically by HIV infection,and is further increased by opportunistic infections, and that thechronic loss of Trp initiates mechanisms responsible for cachexia,dementia and diarrhea and possibly immunosuppression of AIDS patients(Brown, et al., 1991, Adv. Exp. Med. Biol, 294: 425-35). To this end, ithas recently been shown that IDO inhibition can enhance the levels ofvirus-specific T cells and, concomitantly, reduce the number ofvirally-infected macrophages in a mouse model of HIV (Portula et al.,2005, Blood, 106: 2382-90).

IDO is believed to play a role in the immunosuppressive processes thatprevent fetal rejection in utero. More than 40 years ago, it wasobserved that, during pregnancy, the genetically disparate mammalianconceptus survives in spite of what would be predicted by tissuetransplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7:320-38).

Anatomic separation of mother and fetus and antigenic immaturity of thefetus cannot fully explain fetal allograft survival. Recent attentionhas focused on immunologic tolerance of the mother. Because IDO isexpressed by human syncytiotrophoblast cells and systemic tryptophanconcentration falls during normal pregnancy, it was hypothesized thatIDO expression at the maternal-fetal interface is necessary to preventimmunologic rejection of the fetal allografts. To test this hypothesis,pregnant mice (carrying syngeneic or allogeneic fetuses) were exposed toIMT, and a rapid, T cell-induced rejection of all allogeneic conceptionwas observed. Thus, by catabolizing tryptophan, the mammalian conceptusappears to suppress T-cell activity and defends itself againstrejection, and blocking tryptophan catabolism during murine pregnancyallows maternal T cells to provoke fetal allograft rejection (Moan, etal., 1998, Science, 281: 1191-3).

Further evidence for a tumoral immune resistance mechanism based ontryptophan degradation by IDO comes from the observation that most humantumors constitutively express IDO, and that expression of IDO byimmunogenic mouse tumor cells prevents their rejection by preimmunizedmice. This effect is accompanied by a lack of accumulation of specific Tcells at the tumor site and can be partly reverted by systemic treatmentof mice with an inhibitor of IDO, in the absence of noticeable toxicity.Thus, it was suggested that the efficacy of therapeutic vaccination ofcancer patients might be improved by concomitant administration of anIDO inhibitor (Uyttenhove et al., 2003, Nature Med., 9: 1269-74). It hasalso been shown that the IDO inhibitor, 1-MT, can synergize withchemotherapeutic agents to reduce tumor growth in mice, suggesting thatIDO inhibition may also enhance the anti-tumor activity of conventionalcytotoxic therapies (Muller et al, 2005, Nature Med., 11: 312-9).

One mechanism contributing to immunologic unresponsiveness toward tumorsmay be presentation of tumor antigens by tolerogenic host APCs. A subsetof human IDO-expressing antigen-presenting cells (APCs) that coexpressedCD 123 (IL3RA) and CCR6 and inhibited T-cell proliferation have alsobeen described. Both mature and immature CD123-positive dendritic cellssuppressed T-cell activity, and this IDO suppressive activity wasblocked by 1MT (i, et al, 2002, Science, 297: 1867-70). It has also beendemonstrated that mouse tumor-draining lymph nodes (TDLNs) contain asubset of plasmacytoid dendritic cells (pDCs) that constitutivelyexpress immunosuppressive levels of IDO. Despite comprising only 0.5% oflymph node cells, in vitro, these pDCs potently suppressed T cellresponses to antigens presented by the pDCs themselves and also, in adominant fashion, suppressed T cell responses to third-party antigenspresented by nonsuppressive APCs. Within the population of pDCs, themajority of the functional IDO-mediated suppressor activity segregatedwith a novel subset of pDCs coexpressing the B-lineage marker CD19.Thus, it was hypothesized that IDO-mediated suppression by pDCs in TDLNscreates a local microenvironment that is potently suppressive of hostantitumor T cell responses (Munn, et al., 2004, J. Clin. Invest, 114(2):280-90).

IDO degrades the indole moiety of tryptophan, serotonin and melatonin,and initiates the production of neuroactive and immunoregulatorymetabolites, collectively known as kynurenines. By locally depletingtryptophan and increasing proapoptotic kynurenines, IDO expressed bydendritic cells (DCs) can greatly affect T-cell proliferation andsurvival. IDO induction in DCs could be a common mechanism of deletionaltolerance driven by regulatory T cells. Because such tolerogenicresponses can be expected to operate in a variety of physiopathologicalconditions, tryptophan metabolism and kynurenine production mightrepresent a crucial interface between the immune and nervous systems(Grohmann, et al, 2003, Trends Immunol, 24: 242-8). In states ofpersistent immune activation, availability of free serum Trp isdiminished and, as a consequence of reduced serotonin production,serotonergic functions may also be affected (Wirleitner, et al., 2003,Curr. Med. Chem., 10: 1581-91).

In light of the experimental data indicating a role for IDO inimmunosuppression, tumor resistance and/or rejection, chronicinfections, HIV-infection, AIDS (including its manifestations such ascachexia, dementia and diarrhea), autoimmune diseases or disorders (suchas rheumatoid arthritis), and immunologic tolerance and prevention offetal rejection in utero, therapeutic agents aimed at suppression oftryptophan degradation by inhibiting IDO activity are desirable.Inhibitors of IDO can be used to activate T cells and therefore enhanceT cell activation when the T cells are suppressed by pregnancy,malignancy or a virus such as HIV.

Inhibition of IDO may also be an important treatment strategy forpatients with neurological or neuropsychiatric diseases or disorderssuch as depression. Compounds disclosed herein are useful in thepotential treatment or prevention of IDO-related diseases.

SUMMARY OF THE INVENTION

Disclosed herein are novel compounds of formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii) (Ij) and (Ik) which are inhibitors ofthe IDO enzymes. Also disclosed herein are uses of these compounds inthe potential treatment or prevention of an IDO-associated disease ordisorder. Also disclosed herein are compositions comprising one or moreof the compounds. Further disclosed herein are uses of thesecompositions in the potential prevention or treatment of anIDO-associated disease or disorder.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein is a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof:

-   wherein:-   m is 0, 1, 2, 3, 4 or 5;-   p is 0, 1, 2, 3, 4 or 5;-   each occurrence of W is independently selected from (a)    R^(a)R^(b), (b) —NR^(a)—, (c) —C(O)— and (d) —O—(CR^(a)R^(b))_(r)—;    wherein r is 1, 2 or 3; each occurrence of R^(a) and R^(b) is    independently selected from the group consisting of (a)    hydrogen, (b) halogen and (c) C₁₋₆ alkyl, optionally substituted    with 1 to 3 halogens;-   X is selected from —NR^(c)—, —S— and —O—; R^(c) is selected from (a)    hydrogen and (b) C₁₋₆ alkyl;

“

” is an optional double bond; provided that when “

” is a double bond, then the W attached to the double bond is ═CR^(a)—and one R² on the adjacent carbon is absent;

-   each occurrence of R¹ is independently selected from the group    consisting of (a) hydrogen, (b) halogen, (c) —CN, (d) C₁₋₆ alkyl,    optionally substituted with 1 to 3 halogens, (e) C₃₋₆    cycloalkyl, (f) OCHF₂, (g) OCF₃, (h) SCF₃, and (i) SF₅;-   each occurrence of R² is independently selected from the group    consisting of (a) hydrogen, (b) halogen, (c) —OH and (d) C₁₋₆ alkyl,    optionally substituted with 1 to 3 halogens;-   or two R² groups together with the carbon to which they are attached    form a C₃₋₆ cycloakyl or 4-, 5-, or 6-membered heterocycle;-   or R² and R⁵ together with the carbon and sulfur atoms to which they    are attached form a 4-, 5- or 6-membered heterocycle;-   or R² and R^(a) of W together with the carbon and/or nitrogen atoms    to which they are attached form a 4-, 5- or 6-membered carbocycle or    heterocycle;-   R⁴ is selected from the group consisting of (a) hydrogen and (b)    C₁₋₆ alkyl;-   R⁵ is selected from the group consisting of (a) C₁₋₆ alkyl    optionally substituted with —OH, (b) C₃₋₆ cycloalkyl, (c) aryl    and (d) 4-, 5- or 6-membered heterocycle; and-   R⁶ is selected from the group consisting of (a) hydrogen, (b)    —CN, (c) —C(O)—NH₂ and (d) C₁₋₆ alkyl.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof:

-   m is 0, 1, 2 or 3; p is 0, 1 or 2;-   “    ” is a single bond;-   X is selected from —NH—, —S— and —O—;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) halogen;-   each occurrence of R² is independently selected from (a)    hydrogen (b) —OH and (c) C₁₋₄ alkyl;-   R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl;-   R⁵ is selected from (a) C₁₋₄ alkyl optionally substituted with —OH    and (b) C₃₋₆ cycloalkyl; and-   R⁶ is selected from (a) hydrogen, (b) C₁₋₄ alkyl, (c) —CN and (d)    —C(O)—NH₂.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ia):

-   wherein: m is 1, 2, 3 or 4;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) halogen;-   each occurrence of R² is independently selected from (a)    hydrogen (b) —OH and (c) C₁₋₄ alkyl;-   R⁵ is C₁₋₄ alkyl optionally substituted with —OH; and-   R⁶ is selected from (a) hydrogen, (b) C₁₋₄ alkyl, (c) —CN and (d)    —C(O)—NH₂.

In one embodiment of a compound of formula (Ia):

-   m is 2, 3 or 4;-   each occurrence of R¹ is independently selected from (a)    hydrogen, (b) Cl and (c) F;-   each occurrence of R² is independently selected from (a)    hydrogen, (b) —OH, (c) methyl, (d) ethyl and (e) propyl;-   R⁵ is selected from (a) methyl, (b) ethyl and (c) propyl; and-   R⁶ is selected from (a) hydrogen, (b) methyl, (c) ethyl, (d) —CN    and (e) —C(O)—NH₂.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ib):

-   wherein: m is 2, 3 or 4;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) F;-   each occurrence of R² is independently selected from (a)    hydrogen, (b) —OH and (c) methyl;-   R⁵ is selected from (a) methyl, (b) ethyl and (c) C₃₋₆ cycloalkyl;    and-   R⁶ is selected from (a) hydrogen, (b) methyl, (c) —CN and (d)    —C(O)—NH₂.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ic):

-   wherein: p is 0, 1 or 2; q is 0, 1 or 2; r is 1 or 2;-   W is —CR^(a)R^(b)—;-   X is selected from —NH—, —S— and —O—;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) halogen;-   each occurrence of R² is independently selected from (a)    hydrogen, (b) —OH and (c) C₁₋₄ alkyl;-   R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl; and-   R⁶ is selected from (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Id):

-   wherein: p is 0, 1 or 2; r is 1 or 2;-   W is —CR^(a)R^(b)—;-   X is selected from —NH—, —S— and —O—;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) halogen;-   each occurrence of R² is independently selected from (a)    hydrogen, (b) —OH and (c) C₁₋₄ alkyl;-   R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl; and-   R⁶ is selected from (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ie):

wherein: q is 0, 1 or 2; r is 1 or 2; t is 1 or 2;

-   W is selected from the group consisting of CR^(b) and N;-   each occurrence of R^(a) and R^(b) is independently selected from    the group consisting of (a) hydrogen and (b) C₁₋₄ alkyl;-   each of R² is independently selected from (a) hydrogen (b) —OH    and (c) C₁₋₄ alkyl;-   R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl;-   R⁵ is selected from (a) C₁₋₄ alkyl optionally substituted with —OH    and (b) C₃₋₆ cycloalkyl; and-   R⁶ is selected from (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl.

In one embodiment of a compound of formula (Ie):

-   q is 0 or 1; r is 2; t is 2;-   W is N;-   R⁴ is hydrogen;-   R⁵ is selected from (a) methyl, (b) ethyl and (c) C₃₋₆ cycloalkyl;    and-   R⁶ is selected from (a) hydrogen, (b) —CN, (c) methyl and (d) ethyl.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(If):

-   wherein: q is 0, 1, or 2; r is 0 or 1;-   W is selected from the group consisting of —CR^(a)R^(b)— and    —NR^(a)—;-   X is selected from —NH—, —S— and —O—;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) halogen;-   each of R² is independently selected from (a) hydrogen and (b) C₁₋₄    alkyl;-   R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl;-   R⁵ is selected from (a) C₁₋₄ alkyl optionally substituted with —OH    and (b) C₃₋₆ cycloalkyl; and-   R⁶ is selected from (a) hydrogen, (b) —CN, (c) methyl and (d) ethyl.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ig):

-   where m is 0, 1, 2 or 3; n is 1 or 2; p is 1, 2, 3 or 4;-   X is selected from —NH—, —S— and —O—;-   W is selected from the group consisting of —CR^(a)R^(b)—, —NR^(a)—,    and —C(O)—;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) halogen;-   R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl;-   R⁵ is C₁₋₄ alkyl; and-   R⁶ is selected from (a) hydrogen, (b) C₁₋₄ alkyl, (c) —CN and    —C(O)—NH₂.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ih):

-   wherein: q is 1 or 2; r is 1, 2 or 3;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) halogen;-   R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl;-   R⁵ is selected from (a) C₁₋₄ alkyl optionally substituted with —OH    and (b) C₃₋₆ cycloalkyl; and-   R⁶ is selected from (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ii):

-   wherein:-   each occurrence of R¹ is independently selected from (a)    hydrogen (b) Cl and (c) F;-   R⁵ is selected from (a) methyl, (b) ethyl, (c) propyl; and (d) C₃₋₆    cycloalkyl; and-   R⁶ is selected from (a) hydrogen, (b) —CN, (c) methyl, (d)    ethyl, (e) propyl.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ij):

-   wherein: m is 1, 2 or 3; r is 1, 2 or 3;-   each occurrence of R¹ is independently selected from (a) hydrogen    and (b) halogen;-   R⁵ is selected from (a) C₁₋₄ alkyl optionally substituted with —OH    and (b) C₃₋₆ cycloalkyl; and-   R⁶ is selected from (a) hydrogen, (b) C₁₋₄ alkyl, (c) —CN and    —C(O)—NH₂.

In one embodiment of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, the compound is of formula(Ik):

-   wherein: q is 0, 1 or 2; r is 1 or 2; t is 1 or 2; u is 1, 2 or 3;-   W is selected from the group consisting of —CR^(a)R^(b)— and    —NR^(a)—;-   each occurrence of R^(a) and R^(b) is independently selected from    the group consisting of (a) hydrogen and (b) C₁₋₄ alkyl;-   each of R² is independently selected from (a) hydrogen (b) —OH    and (c) C₁₋₄ alkyl;-   R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl;-   R⁵ is selected from (a) C₁₋₄ alkyl optionally substituted with —OH    and (b) C₃₋₆ cycloalkyl; and-   R⁶ is selected from (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl.

In one embodiment, a compound disclosed herein is selected from thegroup consisting of the compounds exemplified in Examples 1 to 33; or apharmaceutically acceptable salt, solvate or hydrate thereof.

Also disclosed herein is a pharmaceutical composition comprising acompound disclosed herein and at least one pharmaceutically acceptablecarrier.

Also disclosed herein is a method of inhibiting activity of indoleamine2,3-dioxygenase (IDO) comprising contacting IDO with a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate orhydrate thereof.

Also disclosed herein is a method of inhibiting immunosuppression in apatient comprising administering to said patient an effective amount ofa compound disclosed herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof.

Also disclosed herein is a method of treating cancer, viral infection,depression, a neurodegenerative disorder, trauma, age-related cataracts,organ transplant rejection, or an autoimmune disease in a patientcomprising administering to said patient an effective amount of acompound disclosed herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof.

Also disclosed herein is a method of treating melanoma in a patientcomprising administering to said patient an effective amount of acompound disclosed herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof.

Further disclosed herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in therapy. In oneembodiment, disclosed herein is the use of a compound disclosed herein,or a pharmaceutically acceptable salt, solvate or hydrate thereof, forthe preparation of a medicament for use in therapy.

As used herein, “alkenyl” refers to both branched- and straight-chainunsaturated aliphatic hydrocarbon groups of 2 to 12 carbon atoms andhaving at least one carbon-carbon double bond. Alkenyl groups may beoptionally substituted with one or more substituents as defined herein.Examples of such groups include, but are not limited to, ethenyl,propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl anddecenyl. “C₂₋₆alkenyl” refers to an alkenyl group as defined hereinhaving 2 to 6 carbon atoms.

“Alkyl” refers to both branched- and straight-chain saturated aliphatichydrocarbon groups of 1 to 18 carbon atoms, or more specifically, 1 to12 carbon atoms. Examples of such groups include, but are not limitedto, methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl,n-hexyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl(i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentyl, and isohexyl.Alkyl groups may be optionally substituted with one or more substituentsas defined herein. “C₁₋₆alkyl” refers to an alkyl group as definedherein having 1 to 6 carbon atoms.

“Aryl” refers to an aromatic monocyclic or multicyclic ring moietycomprising 6 to 14 ring carbon atoms, or more specifically, 6 to 10 ringcarbon atoms. Monocyclic aryl rings include, but are not limited to,phenyl. Multicyclic rings include, but are not limited to, naphthyl andbicyclic rings wherein phenyl is fused to a C₅₋₇cycloalkyl orC₅₋₇cycloalkenyl ring. Aryl groups may be optionally substituted withone or more substituents as defined herein. Bonding can be through anyof the carbon atoms of any ring.

“Halo” or “halogen” refers to fluoro, chloro, bromo or iodo, unlessotherwise noted.

“Heterocycle” or “heterocyclyl” refers to a saturated, partiallyunsaturated or aromatic ring moiety having at least one ring heteroatomand at least one ring carbon atom. In one embodiment, the heteroatom isoxygen, sulfur, or nitrogen. A heterocycle containing more than oneheteroatom may contain different heteroatoms. Heterocyclyl moietiesinclude both monocyclic and multicyclic (e.g., bicyclic) ring moieties.Bicyclic ring moieties include fused, spirocycle and bridged bicyclicrings and may comprise one or more heteroatoms in either of the rings.The ring attached to the remainder of the molecule may or may notcontain a heteroatom. Either ring of a bicyclic heterocycle may besaturated, partially unsaturated or aromatic. The heterocycle may beattached to the rest of the molecule via a ring carbon atom, a ringoxygen atom or a ring nitrogen atom. Non-limiting examples ofheterocycles are described below.

In one embodiment, partially unsaturated and aromatic 4-7 memberedmonocyclic heterocyclyl moieties include, but are not limited to,2,3-dihydro-1,4-dioxinyl, dihydropyranyl, dihydropyrazinyl,dihydropyridazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrotriazolyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, oxoimidazolidinyl, pyranyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydropyrazinyl,tetrahydropyridazinyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, and triazolyl.

In one embodiment, saturated 4-7 membered monocyclic heterocyclylmoieties include, but are not limited to, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, morpholinyl, 1,4-oxazepanyl, oxazolidinyl, oxetanyl,piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl,tetrahydrothienyl, and tetrahydrothiophenyl. In one embodiment, asaturated 4-7 membered monocyclic heterocyclyl is azetidinyl.

Heterocyclic groups may be optionally substituted with one or moresubstituents as defined herein.

“Optionally substituted” refers to “unsubstituted or substituted,” andtherefore, the generic structural formulas described herein encompasscompounds containing the specified optional substituent(s) as well ascompounds that do not contain the optional substituent(s). Eachsubstituent is independently defined each time it occurs within thegeneric structural formula definitions.

Polymorphism

A compound disclosed herein, including a salt, solvate or hydratethereof, may exist in crystalline form, non-crystalline form, or amixture thereof. A compound or a salt or solvate thereof may alsoexhibit polymorphism, i.e. the capacity of occurring in differentcrystalline forms. These different crystalline forms are typically knownas “polymorphs”. Polymorphs have the same chemical composition butdiffer in packing, geometrical arrangement, and other descriptiveproperties of crystalline solid state. Polymorphs, therefore, may havedifferent physical properties such as shape, density, hardness,deformability, stability, and dissolution properties. Polymorphstypically exhibit different melting points, IR spectra, and X-ray powderdiffraction patterns, all of which may be used for identification. Oneof ordinary skill in the art will appreciate that different polymorphsmay be produced, for example, by changing or adjusting the conditionsused in crystallizing/recrystallizing a compound disclosed herein.

Optical Isomers-Diastereomers-Geometric Isomers-Tautomers

Included herein are various isomers of the compounds disclosed herein.The term “isomers” refers to compounds that have the same compositionand molecular weight but differ in physical and/or chemical properties.The structural difference may be in constitution (geometric isomers) orin the ability to rotate the plane of polarized light (stereoisomers).

With regard to stereoisomers, a compound disclosed herein may have oneor more asymmetric carbon atom and may occur as mixtures (such as aracemic mixture) or as individual enantiomers or diastereomers. All suchisomeric forms are included herein, including mixtures thereof. If acompound disclosed herein contains a double bond, the substituent may bein the E or Z configuration. If a compound disclosed herein contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

Any asymmetric atom (e.g., carbon) of a compound disclosed herein, canbe present in racemic mixture or enantiomerically enriched, for examplethe (R)-, (S)- or (R,S)-configuration. In certain embodiments, eachasymmetric atom has at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or(S)-configuration. Substituents at atoms with unsaturated double bondsmay, if possible, be present in cis- (Z)- or trans- (E)-form.

A compound disclosed herein, can be in the form of one of the possibleisomers, rotamers, atropisomers, tautomers or mixtures thereof, forexample, as substantially pure geometric (cis or trans) isomers,diastereomers, optical isomers (antipodes), racemates or mixturesthereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of the final compounds of the examples orintermediates can be resolved into the optical antipodes by knownmethods, e.g., by separation of the diastereomeric salts thereof,obtained with an optically active acid or base, and liberating theoptically active acidic or basic compound. In particular, a basic moietymay thus be employed to resolve the compounds of the present inventioninto their optical antipodes, e.g., by fractional crystallization of asalt formed with an optically active acid, e.g., tartaric acid,dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.Racemic compounds can also be resolved by chiral chromatography, e.g.,high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. For example,compounds including carbonyl —CH₂C(O)— groups (keto forms) may undergotautomerism to form hydroxyl —CH═C(OH)— groups (enol forms). Both ketoand enol forms, individually as well as mixtures thereof, are includedwithin the scope of the present invention.

Isotopic Variations

Compounds disclosed herein, include unlabeled forms, as well asisotopically labeled forms. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compoundsdisclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine, iodine and chlorine, such as ²H (i.e.,Deuterium or “D”), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³⁵S,¹⁸F, ¹²³I, ¹²⁵I and ³⁶Cl. The invention includes various isotopicallylabeled compounds as defined herein, for example those into whichradioactive isotopes, such as ³H and ¹⁴C, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labeled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, substitution with positron emitting isotopes,such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, may be particularly desirable for PET orSPECT studies.

Isotopically-labeled compounds disclosed herein, can generally beprepared by conventional techniques known to those skilled in the art.Furthermore, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index.

Pharmaceutically Acceptable Salts

The term “pharmaceutically acceptable salt” refers to a salt preparedfrom a pharmaceutically acceptable non-toxic base or acid, includinginorganic or organic base and inorganic or organic acid. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includeammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When a compound disclosed herein is basic, a salt may be prepared from apharmaceutically acceptable non-toxic acid, including an inorganic andorganic acid. Such acids include acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroaceticacid (TFA) and the like. Particular embodiments include the citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric,tartaric and trifluoroacetic acids.

Methods of Use

Compounds disclosed herein can inhibit activity of the enzymeindoleamine-2,3-dioxygenase (IDO). For example, the compounds disclosedherein can potentially be used to inhibit activity of IDO in cell or inan individual in need of modulation of the enzyme by administering aneffective amount of a compound. Further disclosed herein are methods ofinhibiting the degradation of tryptophan in a system containing cellsexpressing IDO such as a tissue, living organism, or cell culture. Insome embodiments, the present invention provides methods of altering(e.g., increasing) extracellular tryptophan levels in a mammal byadministering an effective amount of a compound or composition providedherein. Methods of measuring tryptophan levels and tryptophandegradation are routine in the art.

Also disclosed herein are methods of inhibiting immunosuppression suchas IDO-mediated immunosuppression in a patient by administering to thepatient an effective amount of a compound or composition recited herein.IDO-mediated immunosuppression has been associated with, for example,cancers, tumor growth, metastasis, viral infection, viral replication,etc.

Also disclosed herein are methods of treating diseases associated withactivity or expression, including abnormal activity and/oroverexpression, of IDO in an individual (e.g., patient) by administeringto the individual in need of such treatment an effective amount or doseof a compound disclosed herein or a pharmaceutical composition thereof.Example diseases can include any disease, disorder or condition that maybe directly or indirectly linked to expression or activity of the IDOenzyme, such as over expression or abnormal activity. An IDO-associateddisease can also include any disease, disorder or condition that may beprevented, ameliorated, or cured by modulating enzyme activity. Examplesof IDO-associated diseases include cancer, viral infection such as HIVand HCV, depression, neurodegenerative disorders such as Alzheimer'sdisease and Huntington's disease, trauma, age-related cataracts, organtransplantation (e.g., organ transplant rejection), and autoimmunediseases including asthma, rheumatoid arthritis, multiple sclerosis,allergic inflammation, inflammatory bowel disease, psoriasis andsystemic lupus erythematosusor. Example cancers potentially treatable bythe methods herein include cancer of the colon, pancreas, breast,prostate, lung, brain, ovary, cervix, testes, renal, head and neck,lymphoma, leukemia, melanoma, and the like. The compounds of theinvention may also be useful in the treatment of obesity and ischemia.As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the IDO enzyme with a compound disclosed hereinincludes the administration of a compound of the present invention to anindividual or patient, such as a human, as well as, for example,introducing a compound of the invention into a sample containing acellular or purified preparation containing the IDO enzyme.

A subject administered with a compound disclosed herein, or apharmaceutically acceptable salt, solvate or hydrate thereof, isgenerally a mammal, such as a human being, male or female. A subjectalso refers to cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, and birds. In one embodiment, the subject is a human.

As used herein, the terms “treatment” and “treating” refer to allprocesses wherein there may be a slowing, interrupting, arresting,controlling, or stopping of the progression of a disease or disorderthat may be associated with IDO enzyme activity. The terms do notnecessarily indicate a total elimination of all disease or disordersymptoms. The terms also include the potential prophylactic therapy ofthe mentioned conditions, particularly in a subject that is predisposedto such disease or disorder.

The terms “administration of” and or “administering a” compound shouldbe understood to include providing a compound described herein, or apharmaceutically acceptable salt, solvate or hydrate thereof, andcompositions of the foregoing to a subject.

The amount of a compound administered to a subject is an amountsufficient to inhibit IDO enzyme activity in the subject. In anembodiment, the amount of a compound can be an “effective amount”,wherein the subject compound is administered in an amount that willelicit a biological or medical response of a tissue, system, animal orhuman that is being sought by a researcher, veterinarian, medical doctoror other clinician. An effective amount does not necessarily includeconsiderations of toxicity and safety related to the administration of acompound. It is recognized that one skilled in the art may affectphysiological disorders associated with an IDO enzyme activity bytreating a subject presently afflicted with the disorders, or byprophylactically treating a subject likely to be afflicted with thedisorders, with an effective amount of a compound disclosed herein, or apharmaceutically acceptable salt, solvate or hydrate thereof.

An effective amount of a compound will vary with the particular compoundchosen (e.g. considering the potency, efficacy, and/or half-life of thecompound); the route of administration chosen; the condition beingtreated; the severity of the condition being treated; the age, size,weight, and physical condition of the subject being treated; the medicalhistory of the subject being treated; the duration of the treatment; thenature of a concurrent therapy; the desired therapeutic effect; and likefactors and can be routinely determined by the skilled artisan.

The compounds disclosed herein may be administered by any suitable routeincluding oral and parenteral administration. Parenteral administrationis typically by injection or infusion and includes intravenous,intramuscular, and subcutaneous injection or infusion.

The compounds disclosed herein may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound disclosed herein depend on the pharmacokineticproperties of that compound, such as absorption, distribution andhalf-life which can be determined by a skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound disclosed herein depend on the disease orcondition being treated, the severity of the disease or condition, theage and physical condition of the subject being treated, the medicalhistory of the subject being treated, the nature of concurrent therapy,the desired therapeutic effect, and like factors within the knowledgeand expertise of the skilled artisan. It will be further understood bysuch skilled artisans that suitable dosing regimens may requireadjustment given an individual subject's response to the dosing regimenor over time as the individual subject needs change. Typical dailydosages may vary depending upon the particular route of administrationchosen. Typical daily dosages for oral administration, to a humanweighing approximately 70 kg would range from about 0.1 mg to about 2grams, or more specifically, 0.1 mg to 500 mg, or even morespecifically, 0.2 mg to 100 mg, of a compound disclosed herein.

One embodiment of the present invention provides for a method oftreating a disease or disorder associated with IDO enzyme activitycomprising administration of an effective amount of a compound disclosedherein to a subject in need of treatment thereof. In one embodiment, thedisease or disorder associated with an IDO enzyme is a cellproliferation disorder.

In one embodiment, disclosed herein is the use of a compound disclosedherein in a therapy. The compound may be useful in a method ofinhibiting IDO enzyme activity in a subject, such as a mammal in need ofsuch inhibition, comprising administering an effective amount of thecompound to the subject.

In one embodiment, disclosed herein is a pharmaceutical compositioncomprising a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate or hydrate thereof, for use in potential treatment of adisorder or disease related to IDO enzyme activity.

Compositions

The term “composition” as used herein is intended to encompass a dosageform comprising a specified compound in a specified amount, as well asany dosage form which results, directly or indirectly, from combinationof a specified compound in a specified amount. Such term is intended toencompass a dosage form comprising a compound disclosed herein, or apharmaceutically acceptable salt, solvate or hydrate thereof, and one ormore pharmaceutically acceptable carriers or excipients. Accordingly,the compositions of the present invention encompass any composition madeby admixing a compound of the present invention and one or morepharmaceutically acceptable carrier or excipients. By “pharmaceuticallyacceptable” it is meant the carriers or excipients are compatible withthe compound disclosed herein and with other ingredients of thecomposition.

In one embodiment, disclosed herein is a composition comprising acompound disclosed herein, or a pharmaceutically acceptable salt,solvate or hydrate thereof, and one or more pharmaceutically acceptablecarriers or excipients. The composition may be prepared and packaged inbulk form wherein an effective amount of a compound of the invention canbe extracted and then given to a subject, such as with powders orsyrups. Alternatively, the composition may be prepared and packaged inunit dosage form wherein each physically discrete unit contains aneffective amount of a compound disclosed herein. When prepared in unitdosage form, the composition of the invention typically contains fromabout 0.1 mg to 2 grams, or more specifically, 0.1 mg to 500 mg, or evenmore specifically, 0.2 mg to 100 mg, of a compound disclosed herein, ora pharmaceutically acceptable salt, solvate or hydrate thereof.

A compound disclosed herein and a pharmaceutically acceptable carrier orexcipient(s) will typically be formulated into a dosage form adapted foradministration to a subject by a desired route of administration. Forexample, dosage forms include those adapted for (1) oral administration,such as tablets, capsules, caplets, pills, troches, powders, syrups,elixirs, suspensions, solutions, emulsions, sachets, and cachets; and(2) parenteral administration, such as sterile solutions, suspensions,and powders for reconstitution. Suitable pharmaceutically acceptablecarriers or excipients will vary depending upon the particular dosageform chosen. In addition, suitable pharmaceutically acceptable carriersor excipients may be chosen for a particular function that they mayserve in the composition. For example, certain pharmaceuticallyacceptable carriers or excipients may be chosen for their ability tofacilitate the production of uniform dosage forms. Certainpharmaceutically acceptable carriers or excipients may be chosen fortheir ability to facilitate the production of stable dosage forms.Certain pharmaceutically acceptable carriers or excipients may be chosenfor their ability to facilitate the carrying or transporting of acompound disclosed herein, once administered to the subject, from oneorgan or portion of the body to another organ or another portion of thebody. Certain pharmaceutically acceptable carriers or excipients may bechosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, lubricants, binders, disintegrants,fillers, glidants, granulating agents, coating agents, wetting agents,solvents, co-solvents, suspending agents, emulsifiers, sweeteners,flavoring agents, flavor masking agents, coloring agents, anti-cakingagents, hemectants, chelating agents, plasticizers, viscosity increasingagents, antioxidants, preservatives, stabilizers, surfactants, andbuffering agents.

A skilled artisan possesses the knowledge and skill in the art to selectsuitable pharmaceutically acceptable carriers and excipients inappropriate amounts for the use in the invention. In addition, there area number of resources available to the skilled artisan, which describepharmaceutically acceptable carriers and excipients and may be useful inselecting suitable pharmaceutically acceptable carriers and excipients.Examples include Remington's Pharmaceutical Sciences (Mack PublishingCompany), The Handbook of Pharmaceutical Additives (Gower PublishingLimited), and The Handbook of Pharmaceutical Excipients (the AmericanPharmaceutical Association and the Pharmaceutical Press).

The compositions of the invention are prepared using techniques andmethods known to those skilled in the art. Some methods commonly used inthe art are described in Remington's Pharmaceutical Sciences (MackPublishing Company).

In one embodiment, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising an effective amount of a compoundof the invention and a diluent or filler. Suitable diluents and fillersinclude lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g.corn starch, potato starch, and pre-gelatinized starch), cellulose andits derivatives, (e.g. microcrystalline cellulose), calcium sulfate, anddibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch) gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesium stearate, calcium stearate, and talc.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as, for example, by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds disclosed herein may also be coupled with soluble polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyrancopolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example polylactic acid,polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanacrylates and cross-linked oramphipathic block copolymers of hydrogels.

In one embodiment, the invention is directed to a liquid oral dosageform. Oral liquids such as solution, syrups and elixirs can be preparedin dosage unit form so that a given quantity contains a predeterminedamount of a compound disclosed herein. Syrups can be prepared bydissolving the compound of the invention in a suitably flavored aqueoussolution; while elixirs are prepared through the use of a non-toxicalcoholic vehicle. Suspensions can be formulated by dispersing acompound disclosed herein in a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylenesorbitol ethers, preservatives, flavor additives such as peppermint oilor other natural sweeteners or saccharin or other artificial sweetenersand the like can also be added.

In one embodiment, the invention is directed to compositions forparenteral administration. Compositions adapted for parenteraladministration include aqueous and non-aqueous sterile injectionsolutions which may contain anti-oxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Thecompositions may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example water for injections, immediately prior touse. Extemporaneous injection solutions and suspensions may be preparedfrom sterile powders, granules and tablets.

Combinations

A compound disclosed herein may be used in combination with one or moreother active agents, including but not limited to, other anti-canceragents, that are used in the prevention, treatment, control,amelioration, or reduction of risk of a particular disease or condition(e.g., cell proliferation disorders). In one embodiment, a compounddisclosed herein is combined with one or more other anti-cancer agentsfor use in the prevention, treatment, control amelioration, or reductionof risk of a particular disease or condition for which the compoundsdisclosed herein are useful. Such other active agents may beadministered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention.

When a compound disclosed herein is used contemporaneously with one ormore other active agents, a composition containing such other activeagents in addition to the compound disclosed herein is contemplated.Accordingly, the compositions of the present invention include thosethat also contain one or more other active ingredients, in addition to acompound disclosed herein. A compound disclosed herein may beadministered either simultaneously with, or before or after, one or moreother therapeutic agent(s). A compound disclosed herein may beadministered separately, by the same or different route ofadministration, or together in the same pharmaceutical composition asthe other agent(s).

Products provided as a combined preparation include a compositioncomprising a compound disclosed herein and one or more other activeagent(s) together in the same pharmaceutical composition, or a compounddisclosed herein, and one or more other therapeutic agent(s) in separateform, e.g. in the form of a kit.

The weight ratio of a compound disclosed herein to a second active agentmay be varied and will depend upon the effective dose of each agent.Generally, an effective dose of each will be used. Thus, for example,when a compound disclosed herein is combined with another agent, theweight ratio of the compound disclosed herein to the other agent willgenerally range from about 1000:1 to about 1:1000, such as about 200:1to about 1:200. Combinations of a compound disclosed herein and otheractive agents will generally also be within the aforementioned range,but in each case, an effective dose of each active agent should be used.In such combinations, the compound disclosed herein and other activeagents may be administered separately or in conjunction. In addition,the administration of one element may be prior to, concurrent to, orsubsequent to the administration of other agent(s).

In one embodiment, the invention provides a composition comprising acompound disclosed herein, and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease ordisorder associated with IDO enzyme activity.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound disclosed herein. In one embodiment, the kit comprises meansfor separately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

A kit disclosed herein may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist with compliance, akit of the invention typically comprises directions for administration.

Disclosed herein is a use of a compound disclosed herein, for treating adisease or disorder associated with IDO enzyme activity, wherein themedicament is prepared for administration with another active agent. Theinvention also provides the use of another active agent for treating adisease or disorder associated with an IDO enzyme, wherein themedicament is administered with a compound disclosed herein.

The invention also provides the use of a compound disclosed herein fortreating a disease or disorder associated with IDO enzyme activity,wherein the patient has previously (e.g. within 24 hours) been treatedwith another active agent. The invention also provides the use ofanother therapeutic agent for treating a disease or disorder associatedwith IDO enzyme activity, wherein the patient has previously (e.g.within 24 hours) been treated with a compound disclosed herein. Thesecond agent may be applied a week, several weeks, a month, or severalmonths after the administration of a compound disclosed herein.

In one embodiment, the other active agent is selected from the groupconsisting of vascular endothelial growth factor (VEGF) receptorinhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylatingagents, anti-tumor antibiotics, anti-metabolites, retinoids,immunomodulatory agents including but not limited to anti-cancervaccines, CTLA-4, LAG-3 and PD-1 antagonists.

Examples of vascular endothelial growth factor (VEGF) receptorinhibitors include, but are not limited to, bevacizumab (sold under thetrademark AVASTIN by Genentech/Roche), axitinib,(N-methyl-2-[[3-[([pound])-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide,also known as AG013736, and described in PCT Publication No. WO01/002369), Brivanib Alaninate((S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate,also known as BMS-582664), motesanib(N-(2,3-dihydro-3,3-dimethyl-1H-indoi-6-yl)-2-[(4-pyridinyimethyj)amino]-3-pyfidinecarboxamide,and described in PCT Publication No. WO 02/068470), pasireotide (alsoknown as SO 230, and described in PCT Publication No. WO 02/010192), andsorafenib (sold under the tradename NEXAVAR).

Examples of topoisomerase II inhibitors, include but are not limited to,etoposide (also known as VP-16 and Etoposide phosphate, sold under thetradenames TOPOSAR, VEPESID and ETOPOPHOS), and teniposide (also knownas VM-26, sold under the tradename VUMON).

Examples of alkylating agents, include but are not limited to,5-azacytidine (sold under the trade name VIDAZA), decitabine (sold underthe trade name of DECOGEN), temozolomide (sold under the trade namesTEMODAR and TEMODAL by Schering-Plough/Merck), dactinomycin (also knownas actinomycin-D and sold under the tradename COSMEGEN), melphalan (alsoknown as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under thetradename ALKERAN), altretamine (also known as hexamethylmelamine (HMM),sold under the tradename HEXALEN), carmustine (sold under the tradenameBCNU), bendamustine (sold under the tradename TREANDA), busulfan (soldunder the tradenames BUSULFEX and MYLERAN), carboplatin (sold under thetradename PARAPLATIN), lomustine (also known as CCNU, sold under thetradename CeeNU), cisplatin (also known as CDDP, sold under thetradenames PLATINOL and PLATINOL-AQ), chlorambucil (sold under thetradename LEUKERAN), cyclophosphamide (sold under the tradenames CYTOXANand NEOSAR), dacarbazine (also known as DTIC, DIC and imidazolecarboxamide, sold under the tradename DTIC-DOME), altretamine (alsoknown as hexamethylmelamine (HMM) sold under the tradename HEXALEN),ifosfamide (sold under the tradename IFEX), procarbazine (sold under thetradename MATULANE), mechlorethamine (also known as nitrogen mustard,mustine and mechloroethamine hydrochloride, sold under the tradenameMUSTARGEN), streptozocin (sold under the tradename ZANOSAR), thiotepa(also known as thiophosphoamide, TESPA and TSPA, and sold under thetradename THIOPLEX).

Examples of anti-tumor antibiotics include, but are not limited to,doxorubicin (sold under the tradenames ADRIAMYCIN and RUBEX), bleomycin(sold under the tradename LENOXANE), daunorubicin (also known asdauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride,sold under the tradename CERUBIDINE), daunorubicin liposomal(daunorubicin citrate liposome, sold under the tradename DAUNOXOME),mitoxantrone (also known as DHAD, sold under the tradename NOVANTRONE),epirubicin (sold under the tradename ELLENCE), idarubicin (sold underthe tradenames IDAMYCIN, IDAMYCIN PFS), and mitomycin C (sold under thetradename MUTAMYCIN).

Examples of anti-metabolites include, but are not limited to, claribine(2-chlorodeoxyadenosine, sold under the tradename LEUSTATIN),5-fluorouracil (sold under the tradename ADRUCIL), 6-thioguanine (soldunder the tradename PURINETHOL), pemetrexed (sold under the tradenameALIMTA), cytarabine (also known as arabinosylcytosine (Ara-C), soldunder the tradename CYTOSAR-U), cytarabine liposomal (also known asLiposomal Ara-C, sold under the tradename DEPOCYT), decitabine (soldunder the tradename DACOGEN), hydroxyurea (sold under the tradenamesHYDREA, DROXIA and MYLOCEL), fludarabine (sold under the tradenameFLUDARA), floxuridine (sold under the tradename FUDR), cladribine (alsoknown as 2-chlorodeoxyadenosine (2-CdA) sold under the tradenameLEUSTATIN), methotrexate (also known as amethopterin, methotrexatesodium (MTX), sold under the tradenames RHEUMATREX and TREXALL), andpentostatin (sold under the tradename NIPENT).

Examples of retinoids include, but are not limited to, alitretinoin(sold under the tradename PANRETIN), tretinoin (all-trans retinoic acid,also known as ATRA, sold under the tradename VESANOID), Isotretinoin(13-c/s-retinoic acid, sold under the tradenames ACCUTANE, AMNESTEEM,CLARAVIS, CLARUS, DECUTAN, ISOTANE, IZOTECH, ORATANE, ISOTRET, andSOTRET), and bexarotene (sold under the tradename TARGRETIN).

“PD-1 antagonist” means any chemical compound or biological moleculethat blocks binding of PD-L1 expressed on a cancer cell to PD-1expressed on an immune cell (T cell, B cell or NKT cell) and preferablyalso blocks binding of PD-L2 expressed on a cancer cell to theimmune-cell expressed PD-1. Alternative names or synonyms for PD-1 andits ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1,PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC,Btdc and CD273 for PD-L2. In any of the treatment method, medicamentsand uses of the present invention in which a human individual is beingtreated, the PD-1 antagonist blocks binding of human PD-L1 to humanPD-1, and preferably blocks binding of both human PD-L1 and PD-L2 tohuman PD-1. Human PD-1 amino acid sequences can be found in NCBI LocusNo.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be foundin NCBI Locus No.: NP_054862 and NP_079515, respectively.

PD-1 antagonists useful in any of the treatment method, medicaments anduses of the present invention include a monoclonal antibody (mAb), orantigen binding fragment thereof, which specifically binds to PD-1 orPD-L1, and preferably specifically binds to human PD-1 or human PD-L.The mAb may be a human antibody, a humanized antibody or a chimericantibody, and may include a human constant region. In some embodimentsthe human constant region is selected from the group consisting of IgG1,IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, thehuman constant region is an IgG1 or IgG4 constant region. In someembodiments, the antigen binding fragment is selected from the groupconsisting of Fab, Fab′-SH, F(ab′)₂, scFv and Fv fragments. Examples ofPD-1 antagonists include, but are not limited to, pembrolizumab (soldunder the tradename KEYTRUDA) and nivolumab (sold under the tradenameOPDIVO).

Examples of mAbs that bind to human PD-1, and useful in the treatmentmethod, medicaments and uses of the present invention, are described inU.S. Pat. Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,168,757,WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358.

Examples of mAbs that bind to human PD-L1, and useful in the treatmentmethod, medicaments and uses of the present invention, are described inWO2013/019906, WO2010/077634 A1 and U.S. Pat. No. 8,383,796. Specificanti-human PD-L mAbs useful as the PD-1 antagonist in the treatmentmethod, medicaments and uses of the present invention include MPDL3280A,BMS-936559, MEDI4736, MSB0010718C and an antibody which comprises theheavy chain and light chain variable regions of SEQ ID NO:24 and SEQ IDNO:21, respectively, of WO2013/019906.

Other PD-1 antagonists useful in any of the treatment method,medicaments and uses of the present invention include an immunoadhesinthat specifically binds to PD-1 or PD-L1, and preferably specificallybinds to human PD-1 or human PD-L1, e.g., a fusion protein containingthe extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to aconstant region such as an Fc region of an immunoglobulin molecule.Examples of immunoadhesion molecules that specifically bind to PD-1 aredescribed in WO2010/027827 and WO2011/066342. Specific fusion proteinsuseful as the PD-1 antagonist in the treatment method, medicaments anduses of the present invention include AMP-224 (also known as B7-DCIg),which is a PD-L2-FC fusion protein and binds to human PD-1.

Examples of other cytotoxic agents include, but are not limited to,arsenic trioxide (sold under the tradename TRISENOX), asparaginase (alsoknown as L-asparaginase, and Erwinia L-asparaginase, sold under thetradenames ELSPAR and KIDROLASE).

EXPERIMENTAL

The following examples are intended to be illustrative only and notlimiting in any way. Abbreviations used are those conventional in theart or the following.

-   -   ACN acetonitrile    -   ° C. degree Celsius    -   DCM dichloromethane    -   DMA dimethylamine    -   DMF N,N-dimethylformamide    -   DMSO dimethylsulfoxide    -   EtOAc ethyl acetate    -   EtOH ethanol    -   g gram    -   h hour(s)    -   HPLC high pressure liquid chromatography    -   kg kilogram    -   L liter    -   LC liquid chromatography    -   LCMS liquid chromatography and mass spectrometry    -   MeOH methanol    -   MS mass spectrometry    -   MTBE methyl tert-butyl ether    -   min minutes    -   mL milliliter(s)    -   m/z mass to charge ratio    -   nm nanometer    -   nM nanomolar    -   N normal    -   RT or rt room temperature    -   sat. saturated    -   TEA triethyl amine    -   FA trifluoroacetic acid    -   THF tetrahydrofuran

INTERMEDIATES Intermediate A:4-Amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

Malononitrile (15 g, 227 mmol) in 2N HCl (200 mL) was stirred tilldissolved. With the reaction temperature kept between 15° C.-20° C., asolution of sodium nitrite (31.3 g, 454 mmol) in 45 mL of water wasadded dropwise and stirred at ambient for a further 16 h. An aqueoussolution of hydroxylamine hydrochloride (35.0 g, 504 mmol) in 25 mL ofwater was added and the pH of the solution was brought to about 10 byaddition of 10 N NaOH while maintaining the temperature below 20° C. Thetemperature of the reaction was brought to 30° C. for 1 h then refluxedfor 3 h. Heating was discontinued and the reaction gradually cooled toRT overnight. The reaction was cooled in an ice bath, pH adjusted to 8with 6N HCl and stirred for 30 min. The solids were filtered and washedwith cold water to afford the title compound. MS: 144 (M+1). ¹³C NMR(500 MHz, CD3OD): δ 154.5, 144.3, 139.8.

Intermediate B: 4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carbimidoylchloride

To a solution of 4-amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide(5.09 g, 35.6 mmol) in 70 mL of water was added AcOH (35 mL) and 6Nhydrogen chloride (17.78 mL, 107 mmol). The reaction mixture was warmedto 40° C. till all solids were dissolved. The reaction was cooled toambient and solid sodium chloride (6.24 g, 107 mmol) was added, stirred,then the reaction mixture was cooled to 0° C. A solution of sodiumnitrite (2.5 g, 35.6 mmol) in 8.4 mL of water was added dropwise over 3h and the reaction was stirred at 0° C. for a further 1.5 h, then warmedto 15° C. for 15 min. The solid precipitates were filtered and washedwith cold water to afford the title product. MS: 163 (M+1). ¹³C NMR (500MHz, DMSO-d₆): δ 154.4, 142.3, 126.8. ¹HNMR (500 MHz, DMSO-d₆): δ 13.41(s, 1H), 6.29 (s, 2H).

Intermediate C: 4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-aminehydrochloride

Step 1: 3-(2-Bromo-4-fluorophenyl)acrylonitrile

To a solution of 2-bromo-4-fluorobenzaldehyde (400.0 g, 1.97 mol) anddiethyl (cyanomethyl)phosphonate (401.0 g, 2.266 mol) in THF (7 L) wasadded potassium 2-methylpropan-2-olate (254 g, 2.266 mol) portion-wiseat 0° C. After 16 h at 25° C., water (2.5 L) was added and the mixturewas stirred for another 10 min. Layers were separated. The aqueous layerwas extracted with ethyl acetate (1.5 L×3). The combined organic layerswere washed with brine (2.0 L), dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (SiO₂, eluting with petroleum) to give thetitle compound.

Step 2: 3-(2-Bromo-4-fluorophenyl)propanenitrile

To a solution of 3-(2-bromo-4-fluorophenyl)acrylonitrile (160.0 g, 708mmol) in THF (1.5 L) was added LiBH₄ (30.0 g, 1377 mmol) at 0° C. inportions over 5 min. The mixture was stirred at 0° C. for 30 min,followed by the addition of methanol (20 mL) dropwise, warmed to 20° C.,and stirred for 16 h. The mixture was quenched by adding 2.0 M KH₂PO₄aqueous solution until pH ˜7, extracted with ethyl acetate (500 mL×2).The organic layers were washed with brine (100 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (SiO₂,eluting with petroleum ether/ethyl acetate=50:1 to 30:1) to give thetitle compound as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.28-7.40 (m, 2H), 7.04 (td, J=8.0, 2.8 Hz,1H), 3.07 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.2 Hz, 2H).

Step 3: 4-Fluorobicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile

To a stirred solution of diisopropylamine (0.222 L, 1579 mmol) in THF(1.5 L) was added n-BuLi (0.631 L, 2.5 M in hexane, 1579 mmol) dropwiseat −78° C. under N₂ atmosphere. After the addition was finished, thereaction was stirred at −78° C. for 30 min before3-(2-bromo-4-fluorophenyl)propanenitrile (90.0 g, 395 mmol) in THF (500mL) was added dropwise under N₂ atmosphere. The mixture was stirred at−78° C. for 3 h, warmed to RT, quenched with aq. HCl (1.7 L, 1 M) to pH˜8, and extracted by ethyl acetate (500 mL×2). The organic layers werewashed with brine (200 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (SiO₂, eluting with petroleum ether/ethylacetate=50:1 to 30:1) to give the title compound as an oil. ¹H NMR (400MHz, CDCl₃) δ 7.04-7.16 (m, 2H), 6.92-7.00 (m, 1H), 4.21-4.25 (m, 1H),3.62-3.68 (m, 1H), 3.45-3.53 (m, 1H)

Step 4: 4-Fluorobicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid

To a stirred solution of4-fluorobicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (73.0 g, 496mmol) in EtOH (700 mL) and water (140 mL) was added potassium hydroxide(97.0 g, 1736 mmol) at 25° C. After the addition was finished, thereaction mixture was stirred at 80° C. for 1.5 h, cooled to RT, andconcentrated under reduced pressure. The residue was dissolved in water(500 mL) and extracted by DCM (300 mL). The aqueous phase was acidifiedby adding aqueous HCl (6M) to a pH ˜3, then extracted by ethyl acetate(800 mL×2). The organic layers were washed with brine (400 mL), driedover Na₂SO₄, filtered, and concentrated in vacuo to give the titlecompound as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.04-7.07 (m, 1H),6.92-6.97 (m, 2H), 4.30 (t, J=4.0 Hz, 1H), 3.43-3.45 (m, 2H).

Step 5: Tert-Butyl(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)carbamate

To a stirred solution of4-fluorobicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (26.0 g, 156mmol) in t-BuOH (100 mL) were added triethylamine (32.7 mL, 235 mmol)and diphenyl phosphorazidate (51.7 g, 188 mmol). The mixture was stirredat 85° C. for 4 h under N₂ atmosphere, cooled to RT, and concentratedunder reduced pressure. The residue was purified by silicachromatography (petroleum ether/ethyl acetate=50: 1-30:1) to afford thetitle compound. ¹H NMR (400 MHz, CD₃OD) δ 7.07-7.14 (m, 1H), 6.96-7.03(m, 1H), 6.94 (dd, J=7.9, 2.2 Hz, 1H), 5.07 (br s, 1H), 3.54 (br dd,J=14.1, 4.4 Hz, 1H), 2.97 (br d, J=14.1 Hz, 1H), 1.49 (s, 9H).

Step 6: 4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-amine hydrochloride

To a solution of tert-butyl(4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)carbamate (25 g, 105 mmol)in EtOAc (200 mL) was added HCl (100 mL, 4 M in dioxane, 400 mmol) atRT. The mixture was stirred for 2 h at RT (˜26° C.). LCMS and TLC(petroleum ether:ethyl acetate=5:1) showed no starting material. Theprecipitate was collected by filtration to give4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-amine hydrochloride (16.0 g, 92mmol) as a solid. ESI MS m/z 138.1 [M+H+]. ¹H NMR (400 MHz, CD₃OD) δ7.24-7.30 (m, 1H), 7.15-7.22 (m, 1H), 7.12 (dd, J=7.5, 2.2 Hz, 1H),4.79-4.84 (m, 1H), 3.63-3.71 (m, 1H), 3.24 (br d, J=14.5 Hz, 1H).

Intermediates D and E: (S)- and(R)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

Step 1:4-Amino-N-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

To a solution of 4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-aminehydrochloride (15 g, 86 mmol) in EtOH (150 mL) were added4-amino-N-hydroxy-1,2,5-oxadiazole-3-carbimidoyl chloride (16.85 g, 104mmol) and sodium hydrogencarbonate (18.15 g, 216 mmol). The mixture wasstirred at 60° C. for 1 h, cooled to RT, and concentrated in vacuo. Theresidue was purified by silica chromatography (SiO₂, petroleumether/AcOEt: 10:1 to 4:1) to afford the title compound (18.0 g, 68.4mmol) as a solid. LC/MS MS (ESI) m/z: 264.1 [M+H⁺].

Step 2:3-(4-Amino-1,2,5-oxadiazol-3-yl)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of4-amino-N-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide(18.0 g, 68.4 mmol) and CDI (11.09 g, 68.4 mmol) in THF (180 mL) wasadded Et₃N (19.06 mL, 137 mmol). The reaction mixture was stirred at 26°C. for 2 h under N₂ atmosphere (balloon), then concentrated underreduced pressure. The residue was partitioned between water (300 mL) andDCM (300 mL). The aqueous layer was extracted with DCM (300 mL*2). Thecombined organic layers were washed with brine (300 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, Pet.ether/ethyl acetate10:1-3:1 as eluent) to give the title compound (16.5 g, 57.0 mmol) as asolid.

Step 3:4-(4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a stirred solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-1,2,4-oxadiazol-5(4H)-one(15 g, 51.9 mmol) in TFA (1000 mL) was added hydrogen peroxide (174 mL,51.9 mmol, 30%) at 0° C. The reaction was stirred at 15° C. for 15 h,extracted with DCM (1500 mL*8). The organic layers were washed withbrine (200 mL*3), dried over Na₂SO₄, filtered, and concentrated in vacuoto give the title compound as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.05(br d, J=6.6 Hz, 2H), 6.73 (br d, J=6.8 Hz, 1H), 5.65 (br d, J=3.1 Hz,1H), 3.79 (ddd, J=1.5, 5.0, 14.7 Hz, 1H), 3.41 (br d, J=14.8 Hz, 1H)

Step 4: (S)- and(R)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

The above racemic compound was subjected to SFC chiral separation(Column OD 250 mm*50 mm, 10 um; Mobile phase: A: CO₂ B: ethanol;Gradient: 15% B; Flow rate: 180 mL/min). The two chiral intermediates Dand E were obtained as a solid:

Intermediate D (peak 1): ¹H NMR (400 MHz, CDCl₃) δ 7.05 (br d, J=6.6 Hz,2H), 6.73 (br d, J=6.8 Hz, 1H), 5.65 (br d, J=3.1 Hz, 1H), 3.79 (ddd,J=1.5, 5.0, 14.7 Hz, 1H), 3.41 (br d, J=14.8 Hz, 1H)

Intermediate E (peak 2): ¹H NMR (400 MHz, CDCl₃) δ 7.05 (br d, J=6.6 Hz,2H), 6.73 (br d, J=6.8 Hz, 1H), 5.65 (br d, J=3.1 Hz, 1H), 3.79 (ddd,J=1.5, 5.0, 14.7 Hz, 1H), 3.41 (br d, J=14.8 Hz, 1H)

General Synthetic Schemes

The compounds of formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes and synthetic procedures and conditions for the illustrativeintermediates and examples.

In the schemes described below, it is well understood that protectinggroups for sensitive or reactive groups are employed where necessary inaccordance with general principles or chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”,Third edition, Wiley, New York 1999). These groups are removed at aconvenient stage of the compound synthesis using methods that arereadily apparent to those skilled in the art.

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes. An exemplary synthetic scheme is described below.

In Scheme 1, processes for preparing compounds, for example those inExamples 1-11, are described in more detail below in the Examplessection and synthesis of Intermediates A-E.

EXAMPLES Examples 1 and 2.N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((S)—S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((R)—S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

Step 1: Tert-butyl (2-(methylsulfinyl)ethyl)carbamate

To a solution of 2-(methylsulfinyl)ethanamine (638 mg, 5.95 mmol) andtriethylamine (1.66 mL, 11.91 mmol) in THF (20 mL) was addeddi-tert-butyl dicarbonate (1.56 g, 7.14 mmol) at RT. The resultingmixture was stirred at RT for 3 h, diluted with sat. NaHCO₃ solution,and concentrated in vacuo. The residue was extracted with 25% IPA/CHCl₃(50 mL×2). The organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (RediSepRf 24 g column, 0-100% 3:1ethylacetate:ethanol in hexanes) to afford tert-butyl(2-(methylsulfinyl)ethyl)carbamate (900 mg) as an oil.

Step 2: Tert-butyl (2-(S-methylsulfonimidoyl)ethyl)carbamate

To a suspension of the tert-butyl (2-(methylsulfinyl)ethyl)carbamate(0.9 g, 4.34 mmol), 2,2,2-trifluoroacetamide (0.982 g, 8.68 mmol),magnesium oxide (0.717 g, 17.37 mmol), and rhodium(II) acetate dimer(0.077 g, 0.174 mmol) in DCM (43.4 mL) was added iodobenzene diacetate(2.098 g, 6.51 mmol) at RT. The reaction mixture was stirred overnight,and the resulting suspension was filtered through a pad of celite, andthe filtrate was concentrated under reduced pressure. To the solution ofthe resulting residue in MeOH (50 mL) was added potassium carbonate(3.00 g, 21.71 mmol) at RT. The mixture was stirred for 60 min, andconcentrated under reduced pressure. The residue was purified by columnchromatography (RediSepRf 40 g of silica gel, 0-100% 3:1 EA:Ethanol/hex)to give tert-butyl (2-(S-methylsulfonimidoyl)ethyl)carbamate (0.9 g,3.56 mmol) as an oil.

Step 3: (2-Aminoethyl)(imino)(methyl)-l6-sulfanone hydrochloride

To the solution of tert-butyl (2-(S-methylsulfonimidoyl)ethyl)carbamate(270 mg, 1.22 mmol) in 2 mL of dioxane was added a HCl solution indioxane (4.0 M, 1.52 mL, 6.08 mmol) at RT. The reaction mixture wasstirred at RT for 6 h, then concentrated in vacuo to give(2-aminoethyl)(imino)(methyl)-l6-sulfanone hydrochloride (140 mg, 0.882mmol) as a powder, which was used in the next step without furtherpurification.

Step 4:N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

To a solution of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(0.166 g, 0.519 mmol) in THF (5.2 mL) at RT was added a solution of2-(S-methylsulfonimidoyl)ethanamine hydrochloride (140 mg, 0.882 mmol)in DMF (1.0 mL), followed by the addition of triethylamine (0.362 mL,2.60 mmol). The mixture was stirred at RT for 0.5 h before MeOH (1.5 mL)and aqueous NaOH solution (2.0 M, 1.3 mL, 2.60 mmol) were added. Thereaction mixture was stirred at RT for 2 h, and concentrated in vacuo.The residue was treated with TFA (0.200 mL, 2.60 mmol), then partitionedbetween ethyl acetate and sat. NaHCO₃ solution. The organic layer wasseparated, washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by column chromatography(RediSepRf 12 g column, 10-100% (3:1 EtOAc/EtOH) in hexanes) to affordN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide(13 mg, 0.032 mmol) as a powder. LCMS: 369.0 [M+H]+; ¹H NMR (600 MHz,DMSO) δ ppm 10.86 (s, 1H), 7.22 (t, J=6 Hz, 1H), 7.11 (t, J=12 Hz, 1H),6.97 (d, J=12 Hz, 1H), 6.83 (d, J=12 Hz, 1H), 6.70 (t, J=6 Hz, 1H), 5.46(s, 1H), 3.88 (s, 1H), 3.74-3.70 (m, 2H), 3.52 (d, J=12, 1H), 3.46-3.39(m, 2H), 3.25 (d, J=12, 1H), 3.01 (s, 3H).

Step 5.N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((S)—S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((R)—S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

The diastereomericN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide(10 mg, 0.027 mmol) was submitted to chiral SFC separation (Column:Chiralpak, IG, 21×250 (mm); Methanol +0.25% Dimethyl Ethyl Amine; 35% Bin CO₂; Flow rate (mL/min): 70) to afford two chiral isomers (3.5 mgeach) as solids.

Example 1 (peak 1): ¹H NMR (600 MHz, DMSO) δ ppm 10.86 (s, 1H), 7.22 (t,J=6 Hz, 1H), 7.11 (t, J=12 Hz, 1H), 6.97 (d, J=12 Hz, 1H), 6.83 (d, J=12Hz, 1H), 6.70 (t, J=6 Hz, 1H), 5.46 (s, 1H), 3.88 (s, 1H), 3.74-3.70 (m,2H), 3.52 (d, J=12, 1H), 3.46-3.39 (m, 2H), 3.25 (d, J=12, 1H), 3.01 (s,3H).

Example 2 (peak 2): ¹H NMR (600 MHz, DMSO) δ ppm 10.86 (s, 1H), 7.22 (t,J=6 Hz, 1H), 7.11 (t, J=12 Hz, 1H), 6.97 (d, J=12 Hz, 1H), 6.83 (d, J=12Hz, 1H), 6.70 (t, J=6 Hz, 1H), 5.46 (s, 1H), 3.88 (s, 1H), 3.74-3.70 (m,2H), 3.52 (d, J=12, 1H), 3.46-3.39 (m, 2H), 3.25 (d, J=12, 1H), 3.01 (s,3H).

Examples 3 and 4.N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((1R,3s)-1-imino-1-oxido-1λ⁶-thietan-3-yl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((1S,3r)-1-imino-1-oxido-1λ⁶-thietan-3-yl)amino)-1,2,5-oxadiazole-3-carboximidamide

Step 1:(S)-4-(4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(thietan-3-ylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(299 mg, 0.937 mmol) in THF (9.5 mL) at RT were added a solution ofthietan-3-amine hydrobromide (239 mg, 1.41 mmol) in DMF (1.0 mL) andEt₃N (392 μL, 2.81 mmol). The cloudy mixture was stirred at RT for 0.5h, then partitioned between ethyl acetate and sat. NaHCO₃ aqueoussolution. The organic layer was separated, washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography (RediSepRf 24 g column, 10-50% EtOAc/hexanes) togive(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(thietan-3-ylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(192 mg, 0.531 mmol) as a solid.

Step 2:(S)-4-(4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((1-oxidothietan-3-yl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(thietan-3-ylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(95 mg, 0.263 mmol) in DCM (1.4 mL) and MeOH (141 μL) was addedmagnesium monoperoxyphthalate hexahydrate (68.4 mg, 0.138 mmol). Theresulting reaction mixture was stirred at RT for 4 h, diluted withaqueous NaHCO₃ solution, and extracted with ethyl acetate (10 mL×3). Theorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo to afford(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((1-oxidothietan-3-yl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(99 mg, 0.262 mmol) as a solid.

Step 3:N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((1R,3s)-1-imino-1-oxido-1λ⁶-thietan-3-yl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((1S,3r)-1-imino-1-oxido-1λ⁶-thietan-3-yl)amino)-1,2,5-oxadiazole-3-carboximidamide

To a suspension of the(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((1-oxidothietan-3-yl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(100 mg, 0.265 mmol), 2,2,2-trifluoroacetamide (59.9 mg, 0.53 mmol),magnesium oxide (43.8 mg, 1.06 mmol), and rhodium (II) acetate dimer(4.69 mg, 10.60 μmol) in DCM (2.65 mL) was added iodobenzene diacetate(128 mg, 0.398 mmol) at RT. The resulting mixture was stirred at RTovernight, then filtered through a pad of celite. The filtrate wasconcentrated in vacuo. The residue was dissolved in THF (2.0 mL). NaOHaqueous solution (2.0 M, 1.0 mL, 2.0 mmol) was then added at RT. Thereaction mixture was stirred at RT for 60 min, neutralized with 2 mL of1.0 M HCl solution, and partitioned between ethyl acetate and sat.NaHCO₃ solution. The organic layer was washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography (RediSepRf 24 g column, 10-100% (3:1 EtOAc/EtOH)in hexanes) to give both isomers as a white solid.

Example 3 (isomer 1, peak 1, 17 mg): LCMS: 367.1 [M+H]⁺; ¹H NMR (600MHz, DMSO) δ ppm 10.95 (s, 1H), 7.24-7.19 (m, 1H), 7.11 (t, J=6 Hz, 1H),6.99-6.95 (dd, J=6 Hz, 2H), 6.90 (d, J=6 Hz, 1H), 5.44 (s, 1H), 4.69 (s,1H), 4.49-4.36 (m, 3H), 3.98 (d, J=12 Hz, 2H), 3.53 (d, J=12 Hz, 1H),3.25 (d, J=12 Hz, 1H).

Example 4 (isomer 2, peak 2, 10 mg): LCMS: 367.1 [M+H]⁺; ¹H NMR (600MHz, DMSO) δ ppm 10.91 (s, 1H), 7.24-7.19 (m, 1H), 7.11 (t, J=6 Hz, 1H),6.99-6.95 (dd, J=6 Hz, 2H), 6.90 (d, J=6 Hz, 1H), 5.39 (s, 1H), 4.69 (s,1H), 4.39-4.30 (m, 3H), 4.10 (d, J=12 Hz, 2H), 3.51 (d, J=12 Hz, 1H),3.25 (d, J=12 Hz, 1H).

Examples 5 and 6.N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((((1R,3s)-1-imino-1-oxido-1λ⁶-thietan-3-yl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((((1S,3r)-1-imino-1-oxido-1λ⁶-thietan-3-yl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide

Step 1:(S)-4-(4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((thietan-3-ylmethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(105.6 mg, 0.331 mmol) in THF (3.3 mL) at RT was added a solution ofthietan-3-ylmethanamine hydrochloride (69.3 mg, 0.496 mmol) in 0.5 mL ofDMF, followed by the addition of Et₃N (138 μL, 0.992 mmol). The cloudymixture was stirred at RT for 0.5 h, then partitioned between ethylacetate and sat. NaHCO₃ aqueous solution. The organic layer wasseparated, washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The resulting material was purified by columnchromatography (RediSepRf 24 g column, 10-50% EtOAc/hexanes) to give(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((thietan-3-ylmethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(84 mg, 0.224 mmol) as a solid.

Step 2:(S)-4-(4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(((1-oxidothietan-3-yl)methyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((thietan-3-ylmethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(84 mg, 0.224 mmol) in DCM (1.2 mL) and MeOH (120 μL) was addedmagnesium monoperoxyphthalate hexahydrate (58.2 mg, 0.118 mmol). Theresulting reaction mixture was stirred at RT for 4 h, diluted with sat.NaHCO₃ aqueous solution, and extracted with ethyl acetate (10 mL×3). Theorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated to afford(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(((1-oxidothietan-3-yl)methyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(88 mg, 0.225 mmol) as a solid.

Step 3:N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((((1R,3s)-1-imino-1-oxido-1λ⁶-thietan-3-yl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((((1S,3r)-1-imino-1-oxido-1λ⁶-thietan-3-yl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide

To a suspension of the(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(((1-oxidothietan-3-yl)methyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(88 mg, 0.225 mmol), 2,2,2-trifluoroacetamide (50.8 mg, 0.45 mmol),magnesium oxide (37.2 mg, 0.899 mmol), and rhodium (II) acetate dimer(3.98 mg, 8.99 μmol) in DCM (2.2 mL) was added iodobenzene diacetate(109 mg, 0.337 mmol) at RT. The resulting mixture was stirred at RTovernight, then filtered through a pad of celite. The filtrate wasconcentrated in vacuo. The residue was dissolved in THF (2.0 mL). NaOHaqueous solution (2.0 M, 1.0 mL, 2.0 mmol) was then added at RT. Thereaction mixture was stirred at RT for 60 min, neutralized with 2 mL of1.0 M HCl solution, and partitioned between ethyl acetate and sat.NaHCO₃ solution. The organic layer was washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography (RediSepRf 12 g gold column, 10-100% (3:1EtOAc/EtOH) in hexanes) to give both isomers as solids.

Example 5 (isomer 1, peak 1, 23 mg): LCMS: 381.1 [M+H]⁺; ¹H NMR (600MHz, DMSO) δ ppm 10.84 (s, 1H), 7.21 (t, J=6 Hz, 1H), 7.11 (t, J=6 Hz,1H), 6.96 (d, J=6 Hz, 1H), 6.87 (d, J=6 Hz, 1H), 6.66 (t, J=6 Hz, 1H),5.40 (s, 1H), 4.60 (s, 1H), 4.10 (d, J=12 Hz, 2H), 3.76-3.73 (m, 3H),3.57 (d, J=6 Hz, 2H), 3.51 (dd, J=12 Hz, 1H), 3.24 (d, J=12 Hz, 1H).

Example 6 (isomer 2, peak 2, 24 mg): LCMS: 381.1 [M+H]⁺; ¹H NMR (600MHz, DMSO) δ ppm 10.82 (s, 1H), 7.21 (t, J=6 Hz, 1H), 7.11 (t, J=6 Hz,1H), 6.96 (d, J=6 Hz, 1H), 6.87 (d, J=6 Hz, 1H), 6.65 (t, J=6 Hz, 1H),5.40 (s, 1H), 4.49 (s, 1H), 4.-02 (d, J=12 Hz, 2H), 3.84-3.78 (m, 2H),3.56-3.48 (m, 3H), 3.25 (d, J=12 Hz, 1H), 2.91 (m, 1H).

Examples 7 and 8.N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((R)-2-hydroxyethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((S)-2-hydroxyethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

Step 1:(S)-4-(4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((2-hydroxyethyl)thio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(230 mg, 0.721 mmol) in THF (7.2 mL) at RT was added a solution of2-((2-aminoethyl)thio)ethanol (100 mg, 0.825 mmol) in 0.3 mL of DMFfollowed by the addition of Et₃N (0.30 mL, 2.16 mmol). The cloudymixture was stirred at RT for 0.5 h. then partitioned between ethylacetate and sat. NaHCO₃ aqueous solution. The organic layer wasseparated, washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by column chromatography(RediSepRf 12 g column, 10-50% EtOAc/hexanes) to give(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((2-hydroxyethyl)thio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(84 mg, 0.214 mmol) as a solid.

Step 2:4-((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((2-hydroxyethyl)sulfinyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((2-hydroxyethyl)thio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(84 mg, 0.214 mmol) in DCM (1.1 mL) and MeOH (114 μL) was addedmagnesium monoperoxyphthalate hexahydrate (55.6 mg, 0.112 mmol). Theresulting reaction mixture was stirred at RT for 1 h, diluted with sat.NaHCO₃ aqueous solution, and extracted with ethyl acetate (10 mL×3). Theorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated to afford4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((2-hydroxyethyl)sulfinyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(86 mg, 0.210 mmol) as a solid.

Step 3: N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(2-hydroxyethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

To a solution of4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((2-hydroxyethyl)sulfinyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(86 mg, 0.21 mmol) in MeOH (700 μL) were added carbamic acid ammoniasalt (65.6 mg, 0.84 mmol) and iodobenzene diacetate (203 mg, 0.63 mmol).The resulting mixture was stirred at RT for 1 h before MeOH (1.0 mL) andNaOH aqueous solution (2.0 M, 1.0 mL, 2.00 mmol) were added. Thereaction mixture was stirred for another 60 min, then neutralized with 2mL of 1.0 M HCl aqueous solution, and partitioned between ethyl acetateand sat. NaHCO₃ aqueous solution. The organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography (RediSepRf 12 g goldcolumn, 10-100% (3:1 EtOAc/EtOH) in hexanes) to give((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(2-hydroxyethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide(47 mg, 0.118 mmol) as a solid.

Step 4:N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((R)-2-hydroxyethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((S)-2-hydroxyethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

The above obtained diastereomeric mixture was submitted to chiral SFCseparation (Column: IG, 21×250 mm; MeOH w/0.25% DMEA; 35% B in CO₂; Flowrate (mL/min): 70) to afford two chiral isomers as solids.

Example 7 (isomer 1, peak 1, 11.5 mg): LCMS: 399.1 [M+H]⁺; ¹H NMR (600MHz, DMSO) δ ppm 10.86 (s, 1H), 7.25-7.19 (m, 1H), 7.11 (t, J=12 Hz,1H), 6.978 (d, J=6 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 6.70 (t, J=6 Hz, 1H),5.46 (s, 1H), 5.08 (s, 1H), 3.90 (s, 1H), 3.84 (bs, 1H), 3.72 (q, J=6Hz, 2H), 3.51 (dd, J=6 Hz, 1H), 3.43 (q, J=6 Hz, 2H), 3.30-3.17 (m, 3H),

Example 8 (isomer 2, peak 2, 12.6 mg): LCMS: 399.1 [M+H]⁺; ¹H NMR (600MHz, DMSO) δ ppm 10.86 (s, 1H), 7.25-7.19 (m, 1H), 7.11 (t, J=12 Hz,1H), 6.978 (d, J=6 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 6.70 (t, J=6 Hz, 1H),5.46 (s, 1H), 5.08 (s, 1H), 3.86 (s, 1H), 3.84 (bs, 1H), 3.72 (q, J=6Hz, 2H), 3.52 (dd, J=6 Hz, 1H), 3.43 (q, J=6 Hz, 2H), 3.31-3.17 (m, 3H),

Example 9.N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-hydroxy-3-(S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide

Step 1: Tert-butyl (2-hydroxy-3-(methylthio)propyl)carbamate

To a solution of tert-butyl (2-hydroxy-3-mercaptopropyl)carbamate (300mg, 1.45 mmol) in THF (7.2 mL) at 0° C. was added potassiumtert-butoxide (1M in THF, 1.45 mL, 1.45 mmol) slowly. The resultingmixture was stirred for 10 min followed by addition of methyl iodide(100 μL, 1.59 mmol). The resultant white suspension was stirred for 1 h,then partitioned between ethyl acetate and sat. NaHCO₃ aqueous solution.The organic layer was separated, washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by columnchromatography (RediSepRf 24 g column, 10-50% EtOAc/hexanes) to givetert-butyl (2-hydroxy-3-(methylthio)propyl)carbamate (156 mg, 0.705mmol) as an oil.

Step 2: 1-Amino-3-(methylthio)propan-2-ol hydrochloride

To the solution of tert-butyl (2-hydroxy-3-(methylthio)propyl)carbamate(156 mg, 0.705 mmol) in 1.0 mL of dioxane was added HCl (4.0 M indioxane, 0.88 mL, 3.52 mmol) at RT. The resulting mixture was stirredfor 4 h, then concentrated in vacuo to give1-amino-3-(methylthio)propan-2-ol hydrochloride (111 mg, 0.705 mmol) asan oil, which was used in the next step without further purification.

Step 3:4-((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-hydroxy-3-(methylthio)propyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of 1-amino-3-(methylthio)propan-2-ol hydrochloride (111mg, 0.704 mmol) in THF (4.7 mL) at RT were added(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(150 mg, 0.470 mmol) and Et₃N (196 μL, 1.410 mmol). The cloudy mixturewas stirred at RT for 0.5 h, partitioned between ethyl acetate and sat.NaHCO₃ solution. The organic layer was separated, washed with brine,dried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by column chromatography (RediSepRf 12 g column, 10-50%EtOAc/hexanes) to give4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-hydroxy-3-(methylthio)propyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(131 mg, 0.333 mmol) as a solid.

Step 4:4-((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-hydroxy-3-(methylsulfinyl)propyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-hydroxy-3-(methylthio)propyl)amino)-1,2,5-oxladiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(131 mg, 0.333 mmol) in DCM (1.8 mL) and MeOH (178 μL) was addedmagnesium monoperoxyphthalate hexahydrate (87 mg, 0.175 mmol). Theresulting reaction mixture was stirred at RT for 1.5 h, diluted withsat. NaHCO₃ solution, and extracted with ethyl acetate (10 mL×3). Theorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo to afford4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-hydroxy-3-(methylsulfinyl)propyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(129 mg, 0.315 mmol) as a solid.

Step 5: N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-hydroxy-3-(S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide

To a solution of4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-hydroxy-3-(methylsulfinyl)propyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(129 mg, 0.315 mmol) in MeOH (1.0 mL) were added carbamic acid ammoniasalt (98 mg, 1.260 mmol) and iodobenzene diacetate (304 mg, 0.945 mmol).The resulting mixture was stirred at RT for 1 h before MeOH (1.0 mL) andNaOH aqueous solution (2.0 M, 1.0 mL, 2.00 mmol) were added. Thereaction mixture was stirred for another 60 min, then neutralized with 2mL of 1.0 M HCl aqueous solution, and partitioned between ethyl acetateand sat. NaHCO₃ aqueous solution. The organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography (RediSepRf 12 g goldcolumn, 10-100% (3:1 EtOAc/EtOH) in hexanes) to giveN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-hydroxy-3-(S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide(55 mg, 0.138 mmol) as a solid. LCMS: 399.1 [M+H]⁺

Example 10.N—((S)-4-Fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-4-((1-(S-methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazole-3-carboximidamide

Step 1: Methanesulfinic Chloride

To a stirred solution of 1,2-dimethyldisulfane (5.4 g, 57.3 mmol) inacetic acid (6.5 mL) was added sulfuryl dichloride (14.07 ml, 172 mmol)dropwise at −20° C. under N₂ atmosphere. After the addition wasfinished, the reaction was stirred at −20° C. for 1 h, warmed to RT, andstirred for another 2 h. Then acetyl chloride was distilled off from thereaction mixture to afford the crude title compound (4.9 g, 49.7 mmol),which was used in the next step without further purification.

Step 2: N-Tosylmethanesulfonimidoyl Chloride

To a stirred solution of Chloramine-T (11.32 g, 49.7 mmol) in toluene(110 mL) was added a solution of methanesulfinic chloride (4.9 g, 49.7mmol) in toluene (10 mL) dropwise at 0° C. After the addition wasfinished, the reaction was stirred at 80° C. for 5 h, cooled to the roomtemperature. The solid was removed by filtration and washed with drytoluene (100 mL). The filtrate was concentrated in vacuo. The residuewas purified by silica gel chromatography (SiO₂, petroleumether/EtOAc=5:1 to 2:1) to give the title compound (6.5 g, 19.42 mmol)as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.90 (m, 2H), 7.33 (d, J=7.9Hz, 2H), 3.77 (s, 3H), 2.44 (s, 3H).

Step 3: Tert-butyl(1-(S-methyl-N-tosylsulfonimidoyl)piperidin-4-yl)carbamate

To a stirred solution of N-tosylmethanesulfonimidoyl chloride (1000 mg,3.73 mmol) in THF (10 mL) were added tert-butyl piperidin-4-ylcarbamate(748 mg, 3.73 mmol) and Et₃N (0.8 ml, 5.74 mmol) at 20° C. The reactionmixture was stirred at 20° C. for 2 h, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (SiO₂, Petroleumether/EtOAc=5:1 to 1:1) to give the title compound (1.2 g, 2.363 mmol)as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.81-7.87 (m, 2H), 7.27 (br d, J=8.8 Hz, 2H),4.49 (br s, 1H), 3.91 (br d, J=11.0 Hz, 1H), 3.71 (br d, J=11.5 Hz, 1H),3.62 (br s, 1H), 3.04 (s, 3H), 2.89-3.01 (m, 2H), 2.41 (s, 3H), 2.08 (brs, 1H), 2.02 (br s, 1H), 1.44 (s, 9H). ESI MS m/z 332.1 [M−100+H⁺].

Step 4: Tert-Butyl (1-(S-methylsulfonimidoyl)piperidin-4-yl)carbamate

To a suspension of sodium (140 mg, 6.09 mmol) in 10 mL of 1,2-dimethoxyethane was added anthracene (991 mg, 5.56 mmol) and the suspension wasplaced in an ultrasonic cleaner overnight to form a solution. It wasadded to a stirred solution of tert-butyl(1-(S-methyl-N-tosylsulfonimidoyl)piperidin-4-yl) carbamate (800 mg,1.854 mmol) in DME (10 mL) dropwise at 0° C. After the addition wasfinished, the reaction was stirred at 0° C. for 0.5 h, quenched withaqueous HCl (3 N, 3 mL), extracted with DCM (20 mL×2). The aqueous phasewas basified with solid sodium carbonate (200 mg), and concentrated invacuo. The residue was treated with DCM (20 mL), stirred for 1 h. Theinsoluble was removed by filtration. The filtrate was dried over Na₂SO₄,filtered, and concentrated in vacuo to give the title compound (500 mg,1.803 mmol) as a solid. ESI MS m/z 278.1 [M+H⁺].

Step 5: 1-(S-Methylsulfonimidoyl)piperidin-4-amine hydrochloride

To a stirred solution of tert-butyl(1-(S-methylsulfonimidoyl)piperidin-4-yl)carbamate (500 mg, 1.803 mmol)in DCM (5 mL) was added HCl (4 M in dioxane, 5 mL, 20.00 mmol) at 20° C.The reaction was stirred at 20° C. for 1 h, then concentrated in vacuoto give the crude title compound (300 mg) as a solid, which was used inthe next step without further purification. ESI MS m/z 178.1 [M+H⁺].

Step 6:4-((S)-4-Fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-3-(4-((1-(S-methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a stirred solution of 1-(S-methylsulfonimidoyl)piperidin-4-amine (278mg, 0.470 mmol) and Et₃N (0.2 mL, 1.435 mmol) in THF (20 mL) was added(S)-4-(4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(150 mg, 0.470 mmol) at 20° C. The reaction was stirred at 20° C. for 1h, then concentrated in vacuo to give the crude title compound (211 mg)as an oil, which was used in the next step without further purification.ESI MS m/z 450.1[M+H⁺].

Step 7.N—((S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-4-((1-(S-methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazole-3-carboximidamide

To a stirred solution of4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((1-(S-methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(211 mg, 0.469 mmol) in MeOH (10 mL) was added NaOH (2 M aqueoussolution, 1.2 mL, 2.4 mmol) at 20° C. The reaction was stirred at 20° C.for 2 h, neutralized with 2 N HCl aqueous solution to pH ˜7, and thenconcentrated in vacuo, extracted with EtOAc (10 mL*2). The organiclayers were collected, washed with brine (10 mL), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by HPLC on a GILSON 281 instrument fitted with a Waters XSELECTC18 150*30 mm*5 um using water (0.1% TFA)-CH₃CN to give the titlecompound (100 mg) as a solid.

¹H NMR (400 MHz, CD₃OD) δ 7.13 (dd, J=8.0, 4.4 Hz, 1H), 6.96-7.04 (m,1H), 6.89 (br d, J=8.0 Hz, 1H), 5.64 (br d, J=2.7 Hz, 1H), 3.82 (br t,J=11.6 Hz, 2H), 3.64-3.71 (m, 1H), 3.59 (br dd, J=14.1, 4.0 Hz, 1H),3.36 (br d, J=6.6 Hz, 3H), 3.22 (br t, J=10.9 Hz, 2H), 3.02 (br d,J=14.1 Hz, 1H), 2.28 (br d, J=11.9 Hz, 2H), 1.75 (br s, 2H). ESI MS m/z424.1 [M+H⁺].

Example 11.N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(methylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

Step 1: (S)-Tert-butyl(2-((4-(4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)carbamate

To a stirred solution of tert-butyl (2-aminoethyl)carbamate (376 mg,2.35 mmol) and Et₃N (0.45 mL, 3.23 mmol) in THF (10 mL) was added(S)-4-(4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(500 mg, 1.566 mmol) at 20° C. The reaction was stirred at 20° C. for 2h, then concentrated in vacuo. The residue was purified by silica gelchromatography (SiO₂, Petroleum ether/EtOAc=10:1 to 3:1) to give thetitle compound (500 mg) as a solid. ¹H NMR (400 MHz, CD₃OD) δ 7.14-7.20(m, 1H), 7.04-7.11 (m, 1H), 7.00 (br d, J=7.5 Hz, 1H), 6.12 (br s, 1H),3.62-3.76 (m, 2H), 3.39-3.46 (m, 2H), 3.32-3.35 (m, 2H), 1.38-1.46 (m,9H).

Step 2:(S)-3-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-1,2,4-oxadiazol-5(4H)-onehydrochloride

To a stirred solution of tert-butyl(2-((4-(4-(4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)carbamate(500 mg, 1.156 mmol) in 1,4-dioxane (5 mL) was added HCl (4 M indioxane, 5 mL, 20.00 mmol) at 15° C. The reaction was stirred at 15° C.for 2 h, then concentrated in vacuo to give the crude title compound(384 mg) as a solid, which was used directly in the next step withoutpurification. ESI MS m/z: 333.1 [M+H⁺].

Step 3:N-(2-((4-(4-((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)methanesulfonimidamide

To a stirred solution of dichlorotriphenylphosphorane (1388 mg, 4.17mmol) in anhydrous CHCl₃ (10 mL) was added TEA (0.6 mL, 5.21 mmol) at15° C. under N₂ atmosphere. The reaction was stirred at 15° C. for 10min, cooled to 0° C., before N-(tert-butyldimethylsilyl)methanesulfonamide (872 mg, 4.17 mmol) in CHCl₃ (10 mL) was addeddropwise. After the addition was finished, the reaction was stirred at0° C. for 20 min. Then a solution of(S)-3-(4-((2-aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-1,2,4-oxadiazol-5(4H)-onehydrochloride (384 mg, 1.041 mmol) and Et₃N (0.15 mL) in CHCl₃ (10 mL)was added dropwise at 0° C. After the addition was finished, thereaction was stirred at 15° C. for 16 h, then concentrated in vacuo togive the crude title compound (473 mg) as a solid, which was used in thenext step without further purification. ESI m/z: 410.0 [M+H+]

Step 4:N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(methylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

To a solution ofN-(2-((4-(4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)methanesulfonimidamide (473 mg, 1.155 mmol) in MeOH (15 mL) was addedNaOH (2 M aqueous solution, 3.0 mL, 6.0 mmol) at 20° C. The reaction wasstirred at 20° C. for 2 h, neutralized with 2 N HCl aqueous solutionsuntil pH ˜6, and then concentrated in vacuo. The residue was purified byHPLC on a GILSON 281 instrument fitted with a Waters XSELECT C18 150*30mm*5 um using water (0.1% TFA)-CH₃CN to give the title compound (150 mg)as a solid. ESI MS m/z 384.1 [M+H⁺]; ¹H NMR (400 MHz, CD₃OD) δ 7.09-7.15(m, 1H), 7.00 (ddd, J=10.8, 8.3, 2.3 Hz, 1H), 6.85-6.92 (m, 1H), 5.61(br d, J=2.7 Hz, 1H), 3.61-3.79 (m, 1H), 3.51-3.60 (m, 7H), 3.03 (br d,J=14.1 Hz, 1H).

Using the general methodology disclosed in the schemes, Examples 1-11,and general knowledge in organic synthesis, compounds in Table 1 wereprepared.

TABLE 1 Examples 12-29 Ex. # Structure Chemical Name Mass [M + H]+ 12

2-((4-(N-((S)-4- fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxycarbamimidoyl)-1,2,5- oxadiazol-3-yl)amino)-N-(2-(S-methylsulfonimidoyl)ethyl)acetamide 426.1 13

2-((4-(N-((S)-4- fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxycarbamimidoyl)-1,2,5- oxadiazol-3-yl)amino)-N-(2-(S-methylsulfonimidoyl)ethyl)acetamide (chiral, isomer 1) 426.1 14

2-((4-(N-((S)-4- fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxycarbamimidoyl)-1,2,5- oxadiazol-3-yl)amino)-N-(2-(S-methylsulfonimidoyl)ethyl)acetamide (chiral, isomer 2) 426.1 15

4-(((E)-2-(N-cyano-S- methylsulfonimidoyl)vinyl)amino)-N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-1,2,5-oxadiazole- 3-carboximidamide 392.1 16

4-((2-(N-carbamoyl-S- methylsulfonimidoyl)ethyl)amino)-N-((S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-1,2,5-oxadiazole- 3-carboximidamide 412.1 17

4-((2-(N-cyano-S- methylsulfonimidoyl)ethyl)amino)-N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-1,2,5-oxadiazole- 3-carboximidamide 394.1 18

N-((S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-4-((1-(S- methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazole-3- carboximidamide (chiral, isomer 1) 424.119

N-((S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-4-((1-(S- methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazole-3- carboximidamide (chiral, isomer 2) 424.120

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N-hydroxy-4-((1-(S- methylsulfonimidoyl)azetidin-3-yl)amino)-1,2,5-oxadiazole-3- carboximidamide (chiral, isomer 1) 396.121

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((1-(S-methylsulfonimidoyl)azetidin-3- yl)amino)-1,2,5-oxadiazole-3-carboximidamide (chiral, isomer 2) 396.1 22

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((1- imino-1-oxido-1λ⁶-thietan-2-yl)methyl)amino)-1,2,5-oxadiazole-3- carboximidamide (chiral, isomer 1)381.1 23

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((1- imino-l-oxido-1λ⁶-thietan-2-yl)methyl)amino)-1,2,5-oxadiazole-3- carboximidamide (chiral, isomer 2)381.1 24

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((3-(S-methylsulfonimidoyl)propyl)amino)- 1,2,5-oxadiazole-3-carboximidamide(chiral, isomer 1) 383.2 25

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((3-(S-methylsulfonimidoyl)propyl)amino)- 1,2,5-oxadiazole-3-carboximidamide(chiral, isomer 2) 383.1 26

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2- hydroxy-3-(S-methylsulfonimidoyl)propyl)amino)- 1,2,5-oxadiazole-3-carboximidamide(chiral, isomer 1) 399.1 27

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2- hydroxy-3-(S-methylsulfonimidoyl)propyl)amino)- 1,2,5-oxadiazole-3-carboximidamide(chiral, isomer 2) 399.1 28

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2- hydroxy-3-(S-methylsulfonimidoyl)propyl)amino)- 1,2,5-oxadiazole-3-carboximidamide(chiral, isomer 3) 399.1 29

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2- hydroxy-3-(S-methylsulfonimidoyl)propyl)amino)- 1,2,5-oxadiazole-3-carboximidamide(chiral, isomer 4) 399.1

Examples 30 and 31.N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(3-((R)—S-methylsulfonimidoyl)propoxy)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(3-((S)—S-methylsulfonimidoyl)propoxy)-1,2,5-oxadiazole-3-carboximidamide

Step 1:(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(4-(methylthio)butoxy)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of 4-(methylthio)butan-1-ol (113 mg, 0.94 mmol) in 3 mL ofTHF at RT was added potassium 2-methylpropan-2-olate (1 M in THF, 658μL, 0.658 mmol). The mixture was stirred at RT for 10 min before(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(200 mg, 0.627 mmol) in 3 mL of THF was added. The resulting mixture wasstirred at RT for 1 h, partitioned between ethyl acetate and sat. NaHCO₃solution. The organic layer was separated, washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bysilica-gel flash chromatography (RediSepRf 12 g of silica gel, 10-50%EtOAc/hexanes) to afford(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(4-(methylthio)butoxy)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(126 mg, 0.321 mmol) as an oil.

Step 2:4-((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(3-(methylsulfinyl)propoxy)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(3-(methylthio)propoxy)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(140 mg, 0.37 mmol) in DCM (1.7 mL) and MeOH (168 μL) was addedmagnesium monoperoxyphthalate hexahydrate (68.4 mg, 0.138 mmol). Theresulting reaction mixture was stirred at RT for 4 h, and diluted withaqueous NaHCO₃ solution, and extracted with ethyl acetate (10 mL×3). Theorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo to afford the crude title compound (152 mg) as asolid, which was used in the next step without further purification.

Step 3:N—((S)-4-Fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(3-((R)—S-methylsulfonimidoyl)propoxy)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(3-((S)—S-methylsulfonimidoyl)propoxy)-1,2,5-oxadiazole-3-carboximidamide

To a solution of4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-(3-(methylsulfinyl)propoxy)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(152 mg, 0.385 mmol) in MeOH (1.3 mL) were added carbamic acid, ammoniasalt (120 mg, 1.542 mmol) and iodobenzene diacetate (497 mg, 1.542mmol). The resulting mixture was stirred at RT for 1 h before 2 M NaOHaqueous solution (2.0 mL, 4.00 mmol) was added. The mixture was stirredat RT for 60 min, neutralized with addition of 4 mL of 1 M HCl solution,and partitioned between ethyl acetate and sat. NaHCO₃ solution. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by columnchromatography (RediSepRf 12 g gold column, 10-100% (3:1 EtOAc/EtOH) inhexanes) to giveN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(3-(S-methylsulfonimidoyl)propoxy)-1,2,5-oxadiazole-3-carboximidamide(54 mg, 0.141 mmol) as a solid. It was submitted to chiral SFCseparation (Column AD-H, 21×250 mm, Condition MeOH+0.25% DMEA, Flow rate(mL/min): 70) to afford two chiral isomers as solids.

Example 30: (isomer 1, peak 1, 20 mg): LCMS: 384.1 [M+H]⁺; ¹H NMR (600MHz, DMSO-d₆) δ ppm 10.75 (s, 1H), 7.22-7.17 (m, 1H), 7.14-7.06 (m, 1H),7.00 (d, J=6 Hz, 1H), 6.95 (d, J=6 Hz, 1H), 4.99 (s, 1H), 4.54 (t, J=6Hz, 2H), 3.81 (s, 1H), 3.46 (dd, J=6 Hz, 1H), 3.25-3.16 (m, 3H), 2.97(s, 3H), 2.29 (m, 2H).

Example 31 (isomer 2, peak 2, 17 mg): LCMS: 384.1 [M+H]⁺; ¹H NMR (600MHz, DMSO-d₆) δ ppm 10.75 (s, 1H), 7.22-7.17 (m, 1H), 7.14-7.06 (m, 1H),7.00 (d, J=6 Hz, 1H), 6.95 (d, J=6 Hz, 1H), 5.00 (s, 1H), 4.54 (t, J=6Hz, 2H), 3.81 (s, 1H), 3.46 (dd, J=6 Hz, 1H), 3.25-3.16 (m, 3H), 2.97(s, 3H), 2.29 (m, 2H).

Using the general methodology disclosed in the schemes, Examples 1-11and 30-31, and general knowledge in organic synthesis, compounds inTable 2 were prepared.

TABLE 2 Examples 32-89 Ex. # Structure Chemical Name Mass [M + H]+ 32

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(4-(S-methylsulfonimidoyl)butoxy)-1,2,5- oxadiazole-3-carboximidamide (chiral,isomer 1) 398.1 33

N-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(4-(S-methylsulfonimidoyl)butoxy)-1,2,5- oxadiazole-3-carboximidamide (chiral,isomer 2) 398.1 34

4-{[2-(N,S- dimethylsulfonimidoyl)ethyl]amino}-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole- 3-carboximidamide (isomer 1)383.1 35

4-{[2-(N,S- dimethylsulfonimidoyl)ethyl]amino}-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole- 3-carboximidamide (isomer 2)383.1 36

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[3-hydroxy-l-(S-methylsulfonimidoyl)azetidin-3- yl]methyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 426.1 37

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[3-hydroxy-1-(S-methylsulfonimidoyl)azetidin-3- yl]methyl{amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 426.1 38

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[4-(S- methylsulfonimidoyl)butyl]amino}-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 397.1 39

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[4-(S- methylsulfonimidoyl)butyl]amino}-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 397.1 40

N-[2-(N,S-dimethylsulfonimidoyl)ethyl]- N~2~-(4-{N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxycarbamimidoyl}-1,2,5- oxadiazol-3-yl)glycinamide 440.1 41

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[1-(S- methylsulfonimidoyl)azetidin-3-yl]oxy}-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 397.1 42

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[1-(S- methylsulfonimidoyl)azetidin-3-yl]oxy}-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 397.1 43

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[1-(S- methylsulfonimidoyl)pyrrolidin-3-yl]amino}-1,2,5-oxadiazole-3- carboximidamide (isomer 1) 410.1 44

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[1-(S- methylsulfonimidoyl)pyrrolidin-3-yl]amino}-1,2,5-oxadiazole-3- carboximidamide (isomer 2) 410.1 45

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[1-(S- methylsulfonimidoyl)pyrrolidin-3-yl]amino}-1,2,5-oxadiazole-3- carboximidamide (isomer 3) 410.1 46

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[1-(S- methylsulfonimidoyl)pyrrolidin-3-yl]amino}-1,2,5-oxadiazole-3- carboximidamide (isomer 4) 410.1 47

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[2-(S-methylsulfonimidoyl)ethoxy]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 413.1 48

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[2-(S-methylsulfonimidoyl)ethoxy]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 413.1 49

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({1-[(S- methylsulfonimidoyl)acetyl]azetidin-3-yl}oxy)-1,2,5-oxadiazole-3- carboximidamide (isomer 1) 439.1 50

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({1-[(S- methylsulfonimidoyl)acetyl]azetidin-3-yl}oxy)-1,2,5-oxadiazole-3- carboximidamide (isomer 2) 439.1 51

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{2-[(S- methylsulfonimidoyl)amino]ethoxy}-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 385.1 52

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{2-[(S- methylsulfonimidoyl)amino]ethoxy}-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 385.1 53

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({4-[(S-methylsulfonimidoyl)amino]butyl}amino)-1,2,5-oxadiazole-3-carboximidamide 412.1 54

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[methyl(S-methylsulfonimidoyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide 398.1 55

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-hydroxy-3-[(S-methylsulfonimidoyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 414.1 56

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-hydroxy-3-[(S-methylsulfonimidoyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 414.1 57

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[N-(2- hydroxyethyl)-S-methylsulfonimidoyl]ethyl}amino)-1,2,5- oxadiazole-3-carboximidamide(isomer 1) 413.1 58

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[N-(2- hydroxyethyl)-S-methylsulfonimidoyl]ethyl}amino)-1,2,5- oxadiazole-3-carboximidamide(isomer 2) 413.1 59

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[(2S)-4-(S- methylsulfonimidoyl)morpholin-2-yl]methyl}amino)-1,2,5-oxadiazole-3- carboximidamide (isomer 1) 440.1 60

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[(2S)-4-(S- methylsulfonimidoyl)morpholin-2-yl]methyl}amino)-1,2,5-oxadiazole-3- carboximidamide (isomer 2) 440.1 61

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({cis-3-[(S-methylsulfonimidoyl)amino]cyclobutyl}oxy)-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 411.1 62

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({cis-3-[(S-methylsulfonimidoyl)amino]cyclobutyl}oxy)-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 411.1 63

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[(2R)-4-(S- methylsulfonimidoyl)morpholin-2-yl]methyl}amino)-1,2,5-oxadiazole-3- carboximidamide (isomer 1) 440.1 64

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[(2R)-4-(S- methylsulfonimidoyl)morpholin-2-yl]methyl}amino)-1,2,5-oxadiazole-3- carboximidamide (isomer 2) 440.1 65

4-{[3-(S- aminosulfonimidoyl)propyl]amino}-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole- 3-carboximidamide 384.1 66

4-({2-[(N,S- dimethylsulfonimidoyl)amino]ethyl}amino)-N-[(7S)-4-fluorobicyclo[4.2.0]octa- 1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 398.1 67

4-({2-[(N,S- dimethylsulfonimidoyl)amino]ethyl}amino)-N-[(7S)-4-fluorobicyclo[4.2.0]octa- 1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 398.1 68

4-{[2-(S- cyclopropylsulfonimidoyl)ethyl]amino}-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole- 3-carboximidamide (isomer 1)395.1 69

4-{[2-(S- cyclopropylsulfonimidoyl)ethyl]amino}-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole- 3-carboximidamide (isomer 2)395.1 70

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[1-(S- methylsulfonimidoyl)azetidin-3-yl]methyl}amino)-1,2,5-oxadiazole-3- carboximidamide (isomer 1) 410.1 71

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[1-(S- methylsulfonimidoyl)azetidin-3-yl]methyl}amino)-1,2,5-oxadiazole-3- carboximidamide (isomer 2) 410.1 72

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[trans-3-(S-methylsulfonimidoyl)cyclobutyl]amino}-1,2,5-oxadiazole-3-carboximidamide (isomer1) 395.1 73

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[trans-3-(S-methylsulfonimidoyl)cyclobutyl]amino}-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 395.1 74

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[6-(S- methylsulfonimidoyl)spiro[3.3]heptan-2-yl]amino}-1,2,5-oxadiazole-3- carboximidamide (isomer 1) 435.1 75

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[6-(S- methylsulfonimidoyl)spiro[3.3]heptan-2-yl]amino}-1,2,5-oxadiazole-3- carboximidamide (isomer 2) 435.1 76

N- [(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-(S- methylsulfonimidoyl)-2-azaspiro[3.3]heptan-6-yl]amino}-1,2,5- oxadiazole-3-carboximidamide(isomer 1) 436.1 77

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-(S- methylsulfonimidoyl)-2-azaspiro[3.3]heptan-6-yl]amino}-1,2,5- oxadiazole-3-carboximidamide(isomer 2) 436.1 78

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-hydroxy-4-(S-methylsulfonimidoyl)butyl]amino}- 1,2,5-oxadiazole-3-carboximidamide(isomer 1) 413.1 79

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-hydroxy-4-(S-methylsulfonimidoyl)butyl]amino}- 1,2,5-oxadiazole-3-carboximidamide(isomer 2) 413.1 80

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-hydroxy-4-(S-methylsulfonimidoyl)butyl]amino}- 1,2,5-oxadiazole-3-carboximidamide(isomer 3) 413.1 81

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-hydroxy-4-(S-methylsulfonimidoyl)butyl]amino}- 1,2,5-oxadiazole-3-carboximidamide(isomer 4) 413.1 82

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({3-[(S-methylsulfonimidoyl)methyl]bicyclo[1.1.1]pentan-1-yl}amino)-1,2,5-oxadiazole-3- carboximidamide (isomer 1) 421.183

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({3-[(S-methylsulfonimidoyl)methyl]bicyclo[1.1.1]pentan-1-yl}amino)-1,2,5-oxadiazole-3- carboximidamide (isomer 2) 421.184

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[S-(2-hydroxypropyl)sulfonimidoyl]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 413.1 85

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[S-(2-hydroxypropyl)sulfonimidoyl]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 413.1 86

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[S-(2-hydroxypropyl)sulfonimidoyl]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 3) 413.1 87

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[S-(2-hydroxypropyl)sulfonimidoyl]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (isomer 4) 413.1 88

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-(S- methylsulfonimidoyl)ethyl]amino}-1,2,5-oxadiazole-3-carboximidamide (isomer 1) 369.1 89

N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-(S- methylsulfonimidoyl)ethyl]amino}-1,2,5-oxadiazole-3-carboximidamide (isomer 2) 369.1

Examples 90 and 91.N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-R-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

Step 1:(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a mixture of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(500 mg, 1.566 mmol) in THF (3133 μL) at ambient temperature was added2-(methylthio)ethanamine (175 μL, 1.880 mmol) and stirred for 2 h. Thesolution was purified directly by column chromatography on C18 (5-95%MeCN/water with 0.1% TFA modifier) to afford(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(508 mg) as a solid. MS: 364.2 (M+1).

Step 2:4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((E)-N-methoxy-S-methylsulfinimidoyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a mixture of(S)-4-(4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(400 mg, 1.101 mmol) in THF (2752 μL)/MeOH (2752 μL) was addedO-methylhydroxylamine hydrochloride (230 mg, 2.75 mmol). The mixture wasstirred for 5 min before iodobenzene diacetate (383 mg, 1.189 mmol) wasadded. After 30 min, the solution was purified directly by columnchromatography on C18 (5-95% MeCN/water with 0.1% TFA modifier) toafford4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((E)-N-methoxy-S-methylsulfinimidoyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(390 mg) as a foam. MS: 409.2 (M+1).

Step 3:4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-(N-methoxy-S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

To a mixture of4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-((E)-N-methoxy-S-methylsulfinimidoyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(325 mg, 0.796 mmol) in acetonitrile (796 μl)/EtOH (3183 μl) at 0° C.was added K₂CO₃ (220 mg, 1.592 mmol) followed by 50% H₂O₂(aq.) (293 μL,4.77 mmol) dropwise. The mixture was stirred at this temp for 1 h beforewarming to RT and stirring for an additional 6 h. The mixture was cooledto 0° C. and acidified using AcOH (0.5 mL). The resulting solution waspurified directly by column chromatography on C18 (5-95% MeCN/water with0.1% TFA modifier) to afford4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-(N-methoxy-S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(46 mg) as a foam. MS: 425.3 (M+1).

Step 4:N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

To a mixture of4-((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-3-(4-((2-(N-methoxy-S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one(45 mg, 0.106 mmol) in THF (707 μL)/Water (353 μl) at ambienttemperature was added 2.0 M NaOH (aq.) (159 μl, 0.318 mmol). The mixturewas stirred for 5 h before acidifying with AcOH (0.5 mL). The resultingsolution was purified directly by column chromatography on C18 (5-95%MeCN/water with 0.1% TFA modifier) to affordN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide(37 mg) as a solid. MS: 399.3 (M+1).

Step 5:N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamideandN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-R-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide

The diastereomericN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide(30 mg, 0.075 mmol) was submitted to chiral SFC separation to afford twochiral isomers as solids.

Example 90 (peak 1): MS: 399.2 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 10.82(s, 1H), 7.18 (dd, J=7.9, 4.6 Hz, 1H), 7.15-7.03 (m, 1H), 6.93 (d, J=7.9Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.58 (d, J=5.5 Hz, 1H), 5.41 (s, 1H),3.67 (d, J=8.5 Hz, 3H), 3.56 (q, J=8.1, 6.6 Hz, 1H), 3.52 (s, 3H), 3.47(dd, J=13.7, 4.9 Hz, 1H), 3.20 (d, J=14.1 Hz, 1H), 3.05 (s, 3H).

Example 91 (peak 2): MS: 399.2 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 10.82(s, 1H), 7.18 (dd, J=7.9, 4.6 Hz, 1H), 7.11-7.03 (m, 1H), 6.93 (d, J=7.7Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.59 (t, J=5.6 Hz, 1H), 5.41 (s, 1H),3.67 (q, J=8.2, 7.0 Hz, 3H), 3.59-3.53 (m, 1H), 3.52 (s, 3H), 3.47 (dd,J=14.1, 4.9 Hz, 1H), 3.20 (d, J=14.1 Hz, 1H), 3.05 (s, 3H).

Biological Assays IDO1 Enzyme Assay

Compounds to be tested were serially diluted in ten 3-fold steps in DMSOstarting from 10 mM DMSO stocks. Compound dilutions or DMSO alone werethen dispensed from the dilution plate into a Greiner black 384-wellassay plate (catalog #781086) using an Echo 555 acoustic liquid handler(Labcyte).

HIS-tagged IDO1 protein was recombinantly expressed in Escherichia coliusing ZYP5052 autoinduction media supplemented with 500 μM deltaaminolevulinic acid for 48 h at 16° C. IDO1 protein was purified usingNi²⁺-affinity resin and size exclusion chromatography. Purified proteinwas then diluted in assay buffer (50 mM Tris pH 7.0, 1% glycerol, 20 μMmethylene blue, 0.05% Tween-20, 20 mM sodium ascorbate, 100 units/mLcatalase to obtain a final IDO1 concentration of 40 nM. IDO1 solution(30 μM) or buffer alone (30 μM) were dispensed to wells of the assayplate using a BioRAPTR liquid dispenser (Beckman Coulter). Assay platescontaining compound and IDO1 enzyme were incubated at RT for 30 min.Afterwards, 10 μL of 400 μM tryptophan in assay buffer were added toeach well of the assay plate using a BioRAPTR liquid dispenser. Plateswere incubated at RT for 60 min and reactions were quenched by additionof 10 μL of 0.5 M methyl isonipecotate in dimethyl sulfoxide. Plateswere sealed and incubated at 37° C. for 4 h or 50° C. for 2 h. Theplates are allowed to cool and then centrifuged for 1 min at 1000×g. Theresulting fluoresence was measured in an Envision plate reader (PerkinElmer) with a 400/25 nm excitation filter and an 510/20 nm emissionfilter.

The fluoresence intensity of each well was corrected for the backgroundobserved in wells that did not receive IDO1 and was expressed as afraction of the intensity observed in wells that received IDO1 enzymeand DMSO only. Potencies were calculated by linear least squares fit tothe four parameter logistic IC₅₀ equation.

IDO1 Cellular Assay in Hela Cells Stimulated with IFNγ

Hela cells were cultured in complete Hela culture medium (90% EMEM, 10%heat-inactivated fetal bovine serum) and expanded to about 1×109 cells.The cells were then collected and frozen down at 10×106 cells/vial in 1mL frozen medium (90% complete Hela culture medium, 10% DMSO)

Compounds to be tested were serially diluted in ten 3-fold steps in DMSOstarting from 10 mM DMSO stocks in Echo low volume plate(s). Compounddilutions or DMSO alone were then dispensed from the dilution plate(s)into Greiner black 384-well assay plate(s) (catalog #781086, 50 nL/well)using an Echo 550 acoustic liquid handler (Labcyte).

Frozen Hela cells were thawed and transferred into Hela assay medium(99% complete Hela culture medium, 1% Pen/Strep) with 20 mL medium/vialof cells. The cells were spun down at 250 g in a table top centrifugefor 5 min and suspended in same volume of Hela assay medium. The cellswere then counted and adjusted to a density of 2×105 cells/ml in Helaassay medium. Sterile L-tryptophan were added to the cells with finalconcentration of 300 uM L-tryptophan. A small aliquot (2 mL/plate) ofHela cells were set aside and were not treated with IFNγ, to serve asthe Max-E control. The rest of Hela cells were added with sterile IFNγ(Cat #285-IF, R & D systems) with a final concentration of 100 ng/mL.

Hela cells with and without IFNγ were dispensed to the respective wellsof 384-well assay plates containing the compounds. The plates wereincubated for about 48 hours at a 37° C., 5% CO₂ incubator. Afterwards,12 μL of 0.5 M methyl isonipecotate in dimethyl sulfoxide were addedinto each well and the plates were sealed and incubated at 37° C.without CO₂ overnight. The plates were centrifuged for 1 min at 200×g.The resulting fluorescence was measured in a Spectramax plate reader(Molecular Devices) with a 400 nm excitation filter and a 510 nmemission filter.

The fluorescence intensity of each well was corrected for the backgroundobserved in wells with non-IFNγ-treated cells and was expressed as afraction of the intensity observed in wells of IFNγ-treated cells andDMSO only. Potencies were calculated by linear least squares fit to thefour parameter logistic IC₅₀ equation.

The biological activity data using the IDO1 enzyme assay and IDO1cellular assay described above are summarized in the table below.Compounds disclosed herein generally have IC₅₀ of about 0.1 nM to about20,000 nM, or more specifically, about 1 nM to about 10,000 nM, or morespecifically, about 5 nM to about 5,000 nM, or more specifically, about10 nM to about 1,000 nM, or still more specifically, about 10 nM toabout 500 nM. Such a result is indicative of the intrinsic activity ofthe compounds in use as an inhibitor of an IDO enzyme. Specific IC₅₀activity data for the exemplified compounds disclosed herein is providedin the following table.

IDO1 Enzyme Assay, IDO1 HELA Cell Ex. No. IC₅₀, nM Assay, IC₅₀, nM 185.99 55.78 2 88.07 60.89 3 119.9 109.5 4 90.63 161.9 5 101.6 168.1 651.03 92.1 8 43.5 30.5 11 38.72 27.4 12 49.27 114.2 13 58.24 95.51 1463.82 102.6 15 165.2 20.13 16 55.15 69.22 17 64.67 53.72 18 68.34 69.919 67.21 62.07 22 137 81.5 23 143 99.4 24 35.4 39.9 25 31.2 42.7 26 53.799.9 27 43.3 129 28 60.7 110 29 70.4 123 30 231 384 31 213 356 32 178241 33 184 288 34 59.82 77.05 35 81.57 43.17 36 85.68 148.2 37 107.8312.3 38 47.15 26.68 39 50.83 35.67 40 237.1 200.6 41 94.01 116.7 4256.78 43.6 43 168.9 156.8 44 220.2 218.7 45 106.8 85.04 46 174.6 153.247 154.5 196.4 48 118.9 143.8 49 112.4 99.5 50 111.1 152.7 51 261.7317.1 52 174.7 148.4 53 69.37 45.06 54 107.8 101.6 55 92.93 117 56 106.8162 57 70.61 109 58 125.2 122.7 59 119.8 128.8 60 233.8 329.3 61 81.63127.7 62 146.5 183.4 63 97.96 73.02 64 82.97 199.7 65 48.18 25.72 6680.76 59.64 67 63.66 140.1 68 59.15 44.57 69 64.6 48.54 70 79.69 41.6271 80.04 72.35 72 49.51 63.5 73 63.89 85.4 74 73.73 32.22 75 90.41 40.2776 39.95 17.56 77 34.15 22.71 78 57.75 74.78 79 77.55 90.96 80 94.5468.46 81 94.99 62.83 82 91.69 81.97 83 81.49 83.87 84 56.8 55.21 8549.51 49.68 86 47.41 40.54 87 46.1 51.89 88 109.5 53.22 89 206.5 98.5690 44.9 53.54 91 47.19 41.78

IDO1 Human Whole Blood Assay

Compounds to be tested were serially diluted in ten 3-fold steps in DMSOstarting from 10 mM. 3 μL of compound dilutions or DMSO alone were thendispensed from the dilution plate into a polypropylene 96-well assayplate containing 97 μL of RPMI using an Echo 555 acoustic liquid handler(Labcyte). LPS and IFNγ was prepared in in RPMI to a 10λ of final conc.(1000 ng/mL), final concentration is 100 ng/mL.

Human whole blood was drawn in sodium heparin coated tubes from healthyinternal donors. Two hundred forty μL of blood was transferred to eachof the wells of a v-bottom 96 well plate. Thirty μL of compound wastransferred from intermediate dilution plate, and incubated for 15 min.Thirty L from stimulants was then transferred to blood and mixedthoroughly. Plate was covered with breathable membrane and incubated at37° C. for overnight (18 h).

On day 2 isotope labeled standard of kynurenine and tryptophan was madein water at 10× concentration and 30 μL was added to the blood at 3 μMfinal concentration. The assay plates were centrifuged at 300×G for 10min with no brake to separate plasma from red blood cells. Sixty μL ofplasma samples was removed without disturbing red blood cells.

Plasma was diluted with RPMI in 1:1 ratio and proteins were precipitatedout with two volume of Acetonitrile. The plates was centrifuged at4000×G for 60 min. Twenty μL of supernatant was carefully transferred toa 384 well plate contain 40 μL of 0.1% formic acid in water and analyzedby LC/MS/MS.

LC/MS/MS analyses were performed using Thermo Fisher's LX4-TSQ QuantumUltra system. This system consists of four Agilent binaryhigh-performance liquid chromatography (HPLC) pumps and a TSQ QuantumUltra triple quadruple MS/MS instrument. For each sample, 5 μL wereinjected onto an Atlantis T3 column (2.1 mm×150 mm, 3 μm particle size)from Waters. The mobile phase gradient pumped at 0.8 mL/min was used toelute the analytes from the column at 25° C. The elution started at 0% Bincreasing linearly to 25% B at 6.5 min, holding at 25% for 1 min,re-equilibrating to 10 min. Mobile phase A consisted of 0.1% formic acidin water. Mobile phase B consisted of 0.1% of formic acid inacetonitrile. Data was acquired in positive mode using a HESI interface.The operational parameters for the TSQ Quantum Ultra instrument were aspray voltage of 4000 V, capillary temperature of 380° C., vaporizertemperature 400° C., shealth gas 60 arbitrary units, Aux gas 20arbitrary units, tube lens 85 and collision gas 1.2 mTorr. SRMchromatograms of kynurenine (QI: 209.2>Q3:94.0) and internal standard(Q1: 215.3>Q3:98.2) were collected for 90 sec. The peak area wasintegrated by Xcalibur Quan software. The ratios between the kynureninegenerated in the reaction and 2D6-Kynurenine spiked-in internal standardwere used to generate percentage inhibition and IC₅₀ values. Compoundswere titrated and IC₅₀'s were calculated by 4 parameter sigmoidal curvefitting formula.

The biological activity data of selective compounds using the IDO1 humanwhole blood assay described above are summarized in the table below.

Ex. No. IDO1 human whole blood assay, IC₅₀, nM 1 426.6 2 386.3 3 1800 41888 5 411.8 6 494.5 15 869.4 16 842.7 17 172.7 36 1638 41 223.7 63 120588 387

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1. A compound of formula (I), or a pharmaceutically acceptable saltthereof:

wherein: m is 0, 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; eachoccurrence of W is independently selected from (a)

CR^(a)R^(b)—, (b) —NR^(a)—, (c) —C(O)— and (d) —O—(CR^(a)R^(b))_(r)—;wherein r is 1, 2 or 3; each occurrence of R^(a) and R^(b) isindependently selected from the group consisting of (a) hydrogen, (b)halogen and (c) C₁₋₆ alkyl, optionally substituted with 1 to 3 halogens;X is selected from —NR^(c)—, —S— and —O—; R^(c) is selected from (a)hydrogen and (b) C₁₋₆ alkyl; “

” is an optional double bond; provided that when “

” is a double bond, then the W attached to the double bond is ═CR^(a)—and one R² on the adjacent carbon is absent; each occurrence of R¹ isindependently selected from the group consisting of (a) hydrogen, (b)halogen, (c) —CN, (d) C₁₋₆ alkyl, optionally substituted with 1 to 3halogens, (e) C₃₋₆ cycloalkyl, (f) OCHF₂, (g) OCF₃, (h) SCF₃, and (i)SF₅; each occurrence of R² is independently selected from the groupconsisting of (a) hydrogen, (b) halogen, (c) —OH and (d) C₁₋₆ alkyl,optionally substituted with 1 to 3 halogens; or two R² groups togetherwith the carbon to which they are attached form a C₃₋₆ cycloakyl or a4-, 5-, or 6-membered heterocycle; or R² and R⁵ together with the carbonand sulfur atoms to which they are attached form a 4-, 5- or 6-memberedheterocycle; or R² and R^(a) of W together with the carbon and/ornitrogen atoms to which they are attached form (a) a 4-, 5- or6-membered carbocycle, (b) a 7-8 membered spiro bicyclic carbocyclyl,(c) a 7-8 membered spiro bicyclic heterocycle, (d) a 5-6 memberedbridged bicyclic carbocyclyl, or (e) a 4-, 5- or 6-membered heterocycle;R⁴ is selected from the group consisting of (a) hydrogen and (b) C₁₋₆alkyl; R⁵ is selected from the group consisting of (a) C₁₋₆ alkyloptionally substituted with —OH, (b) C₃₋₆ cycloalkyl, (c) aryl and (d)4-, 5- or 6-membered heterocycle; and R⁶ is selected from the groupconsisting of (a) hydrogen, (b) —CN, (c) —C(O)—NH₂, (d) C₁₋₆ alkyloptionally substituted with —OH and (e) —O—C₁₋₆ alkyl.
 2. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein m is0, 1, 2 or 3; p is 0, 1 or 2; “

” is a single bond; X is selected from —NH—, —S— and —O—; eachoccurrence of R¹ is independently selected from (a) hydrogen and (b)halogen; each occurrence of R² is independently selected from (a)hydrogen (b) —OH and (c) C₁₋₄ alkyl; R⁴ is selected from (a) hydrogenand (b) C₁₋₄ alkyl; R⁵ is selected from (a) C₁₋₄ alkyl optionallysubstituted with —OH and (b) C₃₋₆ cycloalkyl; and R⁶ is selected from(a) hydrogen, (b) C₁₋₄ alkyl, (c) —CN and (d) —C(O)—NH₂.
 3. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound has formula (Ia):

wherein: m is 1, 2, 3 or 4; each occurrence of R¹ is independentlyselected from (a) hydrogen and (b) halogen; each occurrence of R² isindependently selected from (a) hydrogen (b) —OH and (c) C₁₋₄ alkyl; R⁵is C₁₋₄ alkyl optionally substituted with —OH; and R⁶ is selected from(a) hydrogen, (b) C₁₋₄ alkyl, (c) —CN and (d) —C(O)—NH₂.
 4. The compoundof claim 3, or a pharmaceutically acceptable salt thereof, wherein: m is2, 3 or 4; each occurrence of R¹ is independently selected from (a)hydrogen, (b) Cl and (c) F; each occurrence of R² is independentlyselected from (a) hydrogen, (b) —OH, (c) methyl, (d) ethyl and (e)propyl; R⁵ is selected from (a) methyl, (b) ethyl and (c) propyl; and R⁶is selected from (a) hydrogen, (b) methyl, (c) ethyl, (d) —CN and (e)—C(O)—NH₂.
 5. The compound of claim 3, or a pharmaceutically acceptablesalt thereof, wherein the compound has formula (Ib):

wherein: m is 2, 3 or 4; each occurrence of R¹ is independently selectedfrom (a) hydrogen and (b) F; each occurrence of R² is independentlyselected from (a) hydrogen, (b) —OH and (c) methyl; R⁵ is selected from(a) methyl, (b) ethyl and (c) C₃₋₆ cycloalkyl; and R⁶ is selected from(a) hydrogen, (b) methyl, (c) —CN and (d) —C(O)—NH₂.
 6. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound has formula (Ic):

wherein: p is 0, 1 or 2; q is 0, 1 or 2; r is 1 or 2; W is—CR^(a)R^(b)—; X is selected from —NH—, —S— and —O—; each occurrence ofR¹ is independently selected from (a) hydrogen and (b) halogen; eachoccurrence of R² is independently selected from (a) hydrogen, (b) —OHand (c) C₁₋₄ alkyl; R⁴ is selected from (a) hydrogen and (b) C₁₋₄ alkyl;and R⁶ is selected from (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl.
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound has formula (Id):

wherein: p is 0, 1 or 2; r is 1 or 2; W is —CR^(a)R^(b)—; X is selectedfrom —NH—, —S— and —O—; each occurrence of R¹ is independently selectedfrom (a) hydrogen and (b) halogen; each occurrence of R² isindependently selected from (a) hydrogen, (b) —OH and (c) C₁₋₄ alkyl; R⁴is selected from (a) hydrogen and (b) C₁₋₄ alkyl; and R⁶ is selectedfrom (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl.
 8. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein the compoundhas formula (Ie):

wherein: q is 0, 1 or 2; r is 1 or 2; t is 1 or 2; W is selected fromthe group consisting of CR^(b) and N; each occurrence of R^(a) and R^(b)is independently selected from the group consisting of (a) hydrogen and(b) C₁₋₄ alkyl; each of R² is independently selected from (a) hydrogen(b) —OH and (c) C₁₋₄ alkyl; R⁴ is selected from (a) hydrogen and (b)C₁₋₄ alkyl; R⁵ is selected from (a) C₁₋₄ alkyl optionally substitutedwith —OH and (b) C₃₋₆ cycloalkyl; and R⁶ is selected from (a) hydrogen,(b) —CN and (c) C₁₋₄ alkyl.
 9. The compound of claim 8, or apharmaceutically acceptable salt thereof, wherein: q is 0 or 1; r is 2;t is 2; W is N; R⁴ is hydrogen; R⁵ is selected from (a) methyl, (b)ethyl and (c) C₃₋₆ cycloalkyl; and R⁶ is selected from (a) hydrogen, (b)—CN, (c) methyl and (d) ethyl.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound hasformula (If):

wherein: q is 0, 1, or 2; r is 0 or 1; W is selected from the groupconsisting of —CR^(a)R^(b)— and —NR^(a)—; X is selected from —NH—, —S—and —O—; each occurrence of R¹ is independently selected from (a)hydrogen and (b) halogen; each occurrence of R² is independentlyselected from (a) hydrogen and (b) C₁₋₄ alkyl; R⁴ is selected from (a)hydrogen and (b) C₁₋₄ alkyl; R⁵ is selected from (a) C₁₋₄ alkyloptionally substituted with —OH and (b) C₃₋₆ cycloalkyl; and R⁶ isselected from (a) hydrogen, (b) —CN, (c) methyl and (d) ethyl.
 11. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound has formula (Ig):

where m is 0, 1, 2 or 3; n is 1 or 2; p is 1, 2, 3 or 4; X is selectedfrom —NH—, —S— and —O—; W is selected from the group consisting of—CR^(a)R^(b)—, —NR^(a)—, and —C(O)—; each occurrence of R¹ isindependently selected from (a) hydrogen and (b) halogen; R⁴ is selectedfrom (a) hydrogen and (b) C₁₋₄ alkyl; R⁵ is C₁₋₄ alkyl; and R⁶ isselected from (a) hydrogen, (b) C₁₋₄ alkyl, (c) —CN and —C(O)—NH₂. 12.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound has formula (Ih):

wherein: q is 1 or 2; r is 1, 2 or 3; each occurrence of R¹ isindependently selected from (a) hydrogen and (b) halogen; R⁴ is selectedfrom (a) hydrogen and (b) C₁₋₄ alkyl; R⁵ is selected from (a) C₁₋₄ alkyloptionally substituted with —OH and (b) C₃₋₆ cycloalkyl; and R⁶ isselected from (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl.
 13. The compoundof claim 12, or a pharmaceutically acceptable salt thereof, wherein thecompound has formula (Ii):

wherein: each occurrence of R¹ is independently selected from (a)hydrogen (b) Cl and (c) F; R⁵ is selected from (a) methyl, (b) ethyl,(c) propyl; and (d) C₃₋₆ cycloalkyl; and R⁶ is selected from (a)hydrogen, (b) —CN, (c) methyl, (d) ethyl, (e) propyl.
 14. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound has formula (Ij):

wherein: m is 1, 2 or 3; r is 1, 2 or 3; each occurrence of R¹ isindependently selected from (a) hydrogen and (b) halogen; R⁵ is selectedfrom (a) C₁₋₄ alkyl optionally substituted with —OH and (b) C₃₋₆cycloalkyl; and R⁶ is selected from (a) hydrogen, (b) C₁₋₄ alkyl, (c)—CN and —C(O)—NH₂.
 15. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound has formula (Ik):

wherein: q is 0, 1 or 2; r is 1 or 2; t is 1 or 2; u is 1, 2 or 3; W isselected from the group consisting of —CR^(a)R^(b)— and —NR^(a)—; eachoccurrence of R^(a) and R^(b) is independently selected from the groupconsisting of (a) hydrogen and (b) C₁₋₄ alkyl; each of R² isindependently selected from (a) hydrogen (b) —OH and (c) C₁₋₄ alkyl; R⁴is selected from (a) hydrogen and (b) C₁₋₄ alkyl; R⁵ is selected from(a) C₁₋₄ alkyl optionally substituted with —OH and (b) C₃₋₆ cycloalkyl;and R⁶ is selected from (a) hydrogen, (b) —CN and (c) C₁₋₄ alkyl. 16.The compound of claim 1, or a pharmaceutically acceptable salt thereof,selected from the group consisting of:N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((S)—S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((R)—S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((1R,3s)-1-imino-1-oxido-1λ⁶-thietan-3-yl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((1S,3r)-1-imino-1-oxido-1λ⁶-thietan-3-yl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((((1R,3s)-1-imino-1-oxido-1λ⁶-thietan-3-yl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((((1S,3r)-1-imino-1-oxido-1λ⁶-thietan-3-yl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((R)-2-hydroxyethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-((S)-2-hydroxyethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-hydroxy-3-(S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-4-((1-(S-methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(methylsulfonoamidimidamido)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide,2-((4-(N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxycarbamimidoyl)-1,2,5-oxadiazol-3-yl)amino)-N-(2-(S-methylsulfonimidoyl)ethyl)acetamide,2-((4-(N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxycarbamimidoyl)-1,2,5-oxadiazol-3-yl)amino)-N-(2-((R)—S-methylsulfonimidoyl)ethyl)acetamide,2-((4-(N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxycarbamimidoyl)-1,2,5-oxadiazol-3-yl)amino)-N-(2-((S)—S-methylsulfonimidoyl)ethyl)acetamide,4-(((E)-2-(N-cyano-S-methylsulfonimidoyl)vinyl)amino)-N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide,4-((2-(N-carbamoyl-S-methylsulfonimidoyl)ethyl)amino)-N—((S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide,4-((2-(N-cyano-S-methylsulfonimidoyl)ethyl)amino)-N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-4-((1-((R)—S-methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N′-hydroxy-4-((1-((S)—S-methylsulfonimidoyl)piperidin-4-yl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((1-((S)—S-methylsulfonimidoyl)azetidin-3-yl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((1-((R)—S-methylsulfonimidoyl)azetidin-3-yl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((((2R)-1-imino-1-oxido-1λ⁶-thietan-2-yl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((((2S)-1-imino-1-oxido-1λ⁶-thietan-2-yl)methyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((3-((R)—S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((3-((S)—S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((2R)-2-hydroxy-3-((S)—S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((2R)-2-hydroxy-3-((R)—S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((2S)-2-hydroxy-3-((S)—S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(((2S)-2-hydroxy-3-((R)—S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(3-((R)—S-methylsulfonimidoyl)propoxy)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(3-((S)—S-methylsulfonimidoyl)propoxy)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(4-((R)—S-methylsulfonimidoyl)butoxy)-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-(4-((S)—S-methylsulfonimidoyl)butoxy)-1,2,5-oxadiazole-3-carboximidamide,4-{[2-(N,S-dimethylsulfonimidoyl)ethyl]amino}-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[3-hydroxy-1-(S-methylsulfonimidoyl)azetidin-3-yl]methyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[4-(S-methylsulfonimidoyl)butyl]amino}-1,2,5-oxadiazole-3-carboximidamide,N-[2-(N,S-dimethylsulfonimidoyl)ethyl]-N˜2˜-(4-{N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxycarbamimidoyl}-1,2,5-oxadiazol-3-yl)glycinamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[1-(S-methylsulfonimidoyl)azetidin-3-yl]oxy}-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[1-(S-methylsulfonimidoyl)pyrrolidin-3-yl]amino}-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[2-(S-methylsulfonimidoyl)ethoxy]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({1-[(S-methylsulfonimidoyl)acetyl]azetidin-3-yl}oxy)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{2-[(S-methylsulfonimidoyl)amino]ethoxy}-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({4-[(S-methylsulfonimidoyl)amino]butyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[methyl(S-methylsulfonimidoyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-hydroxy-3-[(S-methylsulfonimidoyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[N-(2-hydroxyethyl)-S-methylsulfonimidoyl]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[(2S)-4-(S-methylsulfonimidoyl)morpholin-2-yl]methyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({cis-3-[(S-methylsulfonimidoyl)amino]cyclobutyl}oxy)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[(2R)-4-(S-methylsulfonimidoyl)morpholin-2-yl]methyl}amino)-1,2,5-oxadiazole-3-carboximidamide,4-{[3-(S-aminosulfonimidoyl)propyl]amino}-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide,4-({2-[(N,S-dimethylsulfonimidoyl)amino]ethyl}amino)-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide,4-{[2-(S-cyclopropylsulfonimidoyl)ethyl]amino}-N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({[1-(S-methylsulfonimidoyl)azetidin-3-yl]methyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[trans-3-(S-methylsulfonimidoyl)cyclobutyl]amino}-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[6-(S-methylsulfonimidoyl)spiro[3.3]heptan-2-yl]amino}-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-(S-methylsulfonimidoyl)-2-azaspiro[3.3]heptan-6-yl]amino}-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-hydroxy-4-(S-methylsulfonimidoyl)butyl]amino}-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({3-[(S-methylsulfonimidoyl)methyl]bicyclo[1.1.1]pentan-1-yl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-4-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-({2-[S-(2-hydroxypropyl)sulfonimidoyl]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide,N-[(7S)-5-fluorobicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N′-hydroxy-4-{[2-(S-methylsulfonimidoyl)ethyl]amino}-1,2,5-oxadiazole-3-carboximidamide,N—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide,andN—((S)-4-fluorobicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-N′-hydroxy-4-((2-(N-methoxy-R-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carboximidamide.17. A composition which comprises an inert carrier and a compound ofclaim 1 or a pharmaceutically acceptable salt thereof.
 18. (canceled)19. A method for treating or preventing an IDO-associated disease ordisorder in a mammalian subject which comprises administering to thesubject an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 20. A method for treating anIDO-associated disease or disorder in a mammalian subject whichcomprises administering to the subject an effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, incombination with another anti-cancer agent.
 21. The method of claim 20,wherein the IDO-associated disease or disorder is a cancer, viralinfection, HCV infection, depression, neurodegenerative disorders,trauma, age-related cataracts, organ transplantation, and autoimmunediseases.
 22. (canceled)
 23. (canceled)